Ultrasound guided opening of blood-brain barrier

ABSTRACT

An ultrasound treatment system operable to deliver ultrasound energy to a patient&#39;s brain, the system comprises a treatment ultrasound transducer comprising a plurality of treatment elements, the treatment ultrasound transducer locatable to deliver ultrasound into the head of the patient. The system further comprises a data store, one or more position sensors configured to detect relative movement between the head of the patient and the treatment ultrasound transducer, and a data processor.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.16/322,437, filed Jan. 31, 2019, which is the U.S. National Stage filingunder 35 U.S.C. § 371 of PCT/US2017/044763, filed Jul. 31, 2017, each ofwhich claims benefit to U.S. Provisional Application No. 62/369,208,filed Aug. 1, 2016, and which are each incorporated herein by referencein their entireties.

BACKGROUND

Drugs are an important treatment modality for a range of diseasesaffecting the brain including brain cancers. Treatment of diseases ofthe brain is challenging in part due to the structure of the blood-brainbarrier. The blood-brain barrier separates circulating blood from otherbrain tissue, and has a highly selective permeability. This barrierprevents about 98% of small molecules and nearly 100% of large moleculesfrom entering the brain from the bloodstream. This makes it difficult totransport drugs to various tissues of the brain, e.g. to tumor sites.

The blood-brain barrier can be caused to open in certain regions bydelivering ultrasonic energy to those regions, thereby increasing thepossibility for a wider range of molecules of different sizes to passfrom the bloodstream into tissues of the brain. This technique may beapplied to allow drugs to be delivered to the brain. In the currentstate-of-the-art techniques to deliver drugs to the brain, magneticresonance imaging (MRI) may be utilized in combination with ultrasoundbased delivery mechanisms. In these techniques, MRI is used to informthe ultrasound based mechanism where within the brain to focusultrasonic energy.

In these techniques, MRI scans are typically obtained at two differentstages. The first stage, called the “pre-operation” or “pre-op” stage,is before the “operation” or “treatment” (the time period where the drugis actively delivered to the patient). The second stage, called“intra-operation” or “intra-op”, is during the operation. Thesetechniques typically require the concurrent operation of MRI scanners toidentify target regions for treatment within a patient's head andultrasound transducer(s) to deliver energy to effect the opening of theblood-brain barrier.

FIG. 1 shows schematically a prior art example drug delivery system 100.Ultrasound system 105 is coupled to ultrasound transducer 110, which islocated adjacent to patient P's head. Ultrasound transducer 110 may besituated so that it can be operated to transmit ultrasonic energy toselected area(s) in patient P's brain. Ultrasound transducer 110 maycomprise one or more ultrasonic elements that are operable to deliverultrasonic energy to a target region. MRI system 120 may include MRIscanner 125 which is operable to provide images of patient P's headduring treatment. Patient P's head is typically placed within bore 135of MRI scanner 125 during scanning. MRI images may be used to controlthe operation of ultrasound system 105 to insonate the target region.Drugs 130 delivered intravenously to patient P may then enter tissues inthe targeted area of patient P's brain.

Reliance on MRI during the delivery of ultrasound reduces the broadapplicability of this technique. MRI scanning typically involvesinserting the patient's body part of interest (here the head) into bore135 of MRI scanner 125. This often involves inserting the patient deepin the bore so that the head is at the center of the MRI scanner. Thetight confines of the bore inhibit the treating physician's freedom inmanipulating various apparatus during treatment, such as ultrasoundtransducer 110.

Further, the above configuration may present significant challenges forthe patient. As an example, some patients may experience extremediscomfort if they are claustrophobic and are forced to be within thebore of the MRI system during treatment. Additionally, it is veryexpensive to acquire and operate an MRI scanner. These high costs limitaccess to MRI scanners.

There remains a need for practical and effective methods, systems andapparatus that can be applied to facilitate the delivery of moleculesacross selected portions of the blood-brain barrier.

SUMMARY

This invention has a number of aspects that may be applied together,individually and in any sub-combination. These include, withoutlimitation:

-   -   Apparatus and methods for selectively opening the blood-brain        barrier in a patient;    -   Apparatus and methods for delivering drugs to the brain of a        patient;    -   Apparatus and methods for registering ultrasound images with        pre-operation images;    -   Apparatus and methods for identifying areas of treatment in a        patient;    -   Apparatus and methods for delivering ultrasound energy to a        patient; and    -   Controllers for apparatus and methods for delivering drugs to        the brain of a patient.

Some aspects of the invention provide systems to deliver ultrasound toone or more regions of the brain.

An example aspect of the invention provides a system operable to deliverultrasound energy to a patient's brain. The ultrasound energy mayfacilitate opening of the blood brain barrier. Delivery of theultrasound energy may be coordinated with delivery of a drug which mayenter the patient's brain upon opening of the blood brain barrier,thereby facilitating treatment. The system comprises: an imagingultrasound transducer; a treatment ultrasound transducer; an ultrasoundmachine connected to operate the imaging ultrasound transducer togenerate one or more ultrasound images; and a data processor. the dataprocessor is configured to: process one of the ultrasound images with acorresponding previously obtained image to register thepreviously-obtained image to the ultrasound image to yield atransformation relating coordinates in a frame of reference of thepreviously obtained image to coordinates in a frame of reference of theultrasound image; using the transformation, determine coordinates of atleast one target region in the frame of reference of the ultrasoundimage; and based on the coordinates of the at least one target region,determine a target location for the treatment ultrasound transducer todeliver ultrasound energy to the at least one target region. The systemmay include a data store in which the previously obtained image may beprovided.

The treatment transducer optionally comprises one or more transducerelements that are connected to transmit ultrasound signals and are notconnected to a receiving circuit. In some embodiments the treatmenttransducer has a frequency of operation lower than a frequency ofoperation of the imaging transducer.

The system may comprise a robotic manipulator connected to selectivelyposition one or both of the imaging transducer and the treatmenttransducer. In such embodiments the imaging ultrasound transducer may becarried by the robotic manipulator and the data processor may beconfigured to control the robotic manipulator to position the imagingultrasound transducer at an imaging location to generate the one or moreimages. The imaging location may correspond to a low attenuationacoustic window in the skull of the patient. In such embodiments thetreatment ultrasound transducer may be carried by the roboticmanipulator and the data processor may be configured to control therobotic manipulator to position the treatment ultrasound transducer at atarget location. The target location may be determined in a frame ofreference of the robotic manipulator using the transformation.

In some embodiments the processor is configured to process thepreviously obtained image to determine a tangent plane to a patient'sskull at the target location and to operate the robotic manipulator toorient the treatment transducer perpendicular to the tangent plane.

In some embodiments the system comprises a sensor outputting one or moreof: position and orientation; the sensor attached to one or more of: theimaging transducer and the treatment transducer; and the data processoris configured to process an output signal from the position sensor todetermine when the treatment transducer is at the target location.

Various forms for the imaging and treatment transducers are possible. Insome embodiments the system comprises a support shaped to define acavity dimensioned to receive a patient's head and a plurality oftransducer elements are distributed over the support. In suchembodiments the imaging ultrasound transducer may comprise a firstsubset of the transducer elements and the treatment ultrasoundtransducer may comprise a second subset of the transducer elements. Thetreatment ultrasound transducer optionally comprises a plurality ofsubsets of the transducer elements each of the plurality of subsetsbeing configured to deliver ultrasound energy to the same target region.The imaging ultrasound transducer optionally comprises a plurality ofsubsets of the transducer elements. The data processor may be configuredto select the second subset of the transducer elements from thetransducer elements based on the target location. The data processor maybe configured to determine a number of the transducer elements toinclude in the second subset of the transducer elements based at leastin part on a distance between the target region and the target location.

The support optionally comprises one or more mechanical sub-structures,each mechanical sub-structure carrying one or more of the transducerelements. Actuators may be coupled to adjust a position and/ororientation of the sub-structure. The system may be configured tocontrol the actuators to place the transducer elements in desiredpositions and orientations, for example to bring the transducer elementsinto contact with a patient's head and/or to orient the transducerelements perpendicular to a tangent plane to the patient's head. Thedata processor may be configured to process the previously obtainedimage to determine a tangent plane to a patient's skull at the targetlocation and to operate the one or more actuators orient thesubstructure such that the transducer elements carried by thesub-structure are oriented perpendicular to the tangent plane.

In some embodiments the data processor is configured to calculate anestimated attenuation of ultrasound travelling between the targetlocation and the target region and to determine at least one of: anumber of the transducer elements to include in the second subset of thetransducer elements and a power level for driving the transducerelements in the second subset of transducer elements based at least inpart on the estimated attenuation.

In some embodiments the system comprises plural (e.g. two or three ormore) treatment transducers and the system is configured to deliverultrasound to the target region by the plural treatment transducers insuccession. This can reduce the buildup of standing waves. In someembodiments each of the plural treatment transducers comprises pluraltransducer elements distributed over an area. The areas of two or moreof the plural treatment transducers may optionally overlap. In someembodiments the system is configured to substantially continuouslyinsonate a target region for a treatment period comprising plural subperiods by operating different sets of one or more of the pluraltreatment transducers in different ones of the sub periods. Each of thetreatment transducers may be controlled to focus ultrasound energy onthe target region. Ultrasound energy may be focused on a target regionthrough the use of beam steering, acoustic lenses and/or othertechniques for concentrating ultrasound as known in the art.

In some embodiments the system comprises a drug delivery system and thedata processor is configured to trigger operation of the drug deliverysystem. For example, the data processor may be configured to triggeroperation of the treatment ultrasound transducer a predetermined timeafter triggering operation of the drug delivery system and/or upondetecting that a drug has been carried in the bloodstream to the targetregion (e.g. by detecting acoustic signatures of microbubbles associatedwith the drug originating from the target region—the treatmentultrasound transducer may emit first ultrasound signals which generatethe acoustic signatures upon interaction with the microbubbles until themicrobubbles are detected and then be switched to delivering ultrasoundenergy to facilitate treatment).

A source of one or more of first and second microbubbles may beconnected to the drug delivery system. The first microbubbles may beconfigured to amplify signals reflected back to the imaging transducer.The second microbubbles may be configured to vibrate or break whenreceiving ultrasound energy from the treatment transducer. The secondmicrobubbles may contain one or more drugs.

The data store may store predetermined treatment ultrasound parametersfor a plurality of drugs. Different ultrasound parameters may be storedfor different drugs or different drug delivery modalities (e.g. with orwithout microbubbles, different types of microbubbles). In someembodiments the ultrasound system comprises a reader operative to readdrug-identification information identifying one of the plurality ofdrugs from a machine-readable tag and the data processor is configuredto use the drug-identification information to retrieve predeterminedtreatment ultrasound parameters corresponding to the one of theplurality of drugs corresponding to the drug-identification information.The reader may comprise, for example a bar code reader, a QR codereader, or a RFID, reader.

Some embodiments comprise an electromagnetic (EM) tracking systemoperative to track a position of one or both of the imaging transducerand the treatment transducer. For example, the EM tracking system maycomprise an EM transmitter and an EM sensor attached to one or more of:the imaging transducer and the treatment transducer.

In some embodiments the data processor is configured to obtain thetransformation by: processing the previously obtained image to obtainreconstructed images along one or more planes and identifying a commonstructure in the reconstructed images and the ultrasound image;determining a correlation value between each of the reconstructed imagesand the ultrasound image, selecting one of the one reconstructed imageshaving the greatest correlation value above a threshold, and assigningthe common structure in the selected reconstructed image coordinates ofthe common structure in the ultrasound image in a frame of reference ofthe ultrasound image. The data processor may be configured to find thecorrelation value by performing one or more of: changing a scale factor,changing an orientation angle and rotating by an angle on one or more ofthe reconstructed images.

Another example aspect of the invention provides a method forconfiguring an ultrasound machine. The method comprises: obtaining anultrasound image that includes one or more structures in a patient'shead using an imaging ultrasound transducer and, by a data processor:registering a previously-obtained image of the patient's head to theultrasound image to yield a transformation relating coordinates in aframe of reference of the previously obtained image to coordinates in aframe of reference of the ultrasound image, wherein thepreviously-obtained image includes the one or more structures; using thetransformation determining coordinates of at least one target region inthe frame of reference of the ultrasound image; and based on thecoordinates of the at least one target region determining a location forat least one ultrasound treatment transducer to deliver ultrasoundenergy to the at least one target region. The one or more structures maycomprise, for example, one or more of: circle of Willis, ventricles,corpus callosum, dental implants, surgical screws, and orthopaedichardware.

In some embodiments obtaining the transformation comprises: processingthe previously obtained image to obtain reconstructed images along oneor more planes and identifying a common structure in the reconstructedimages and the ultrasound image; determining a correlation value betweeneach of the reconstructed images and the ultrasound image, selecting oneof the one reconstructed images having the greatest correlation valueabove a threshold, and assigning the common structure in the selectedreconstructed image coordinates of the common structure in theultrasound image in a frame of reference of the ultrasound image.

The previously obtained image may, for example, comprise a magneticresonance image (MRI) or a computed tomography (CT) image. The methodmay receive user input specifying the location of the target regionrelative to the previously obtained image. Some embodiments involveoperating a robotic manipulator to place the ultrasound imagingtransducer or the ultrasound treatment transducer at the determinedlocation. Other embodiments involve manual placement of the ultrasoundimaging transducer or the ultrasound treatment transducer at thedetermined location by a human operator.

In some embodiments the method comprise configuring a plurality oftransducer elements in the vicinity of the determined location to beoperated as the treatment transducer.

The imaging transducer may be located adjacent to a low attenuationacoustic window in a patient's skull. The low attenuation acousticwindow may, for example, comprise the temple, back of the head or behindan eye of the patient.

Some embodiments comprise commanding a drug delivery system to deliverto the patient microbubbles configured to vibrate or break whenreceiving ultrasound energy from the treatment transducer.

Another example aspect of the invention provides an ultrasoundtransducer assembly comprising: one or more first transducer elements;one or more second transducer elements; one or more electronic channelsoperable to drive the first and second transducer elements to emitultrasound, each of the electronic channels coupled to drive one or moreof the first and second transducer elements; the first transducerelements each coupled to a receive circuit and the second transducerelements not connected to receive circuits. The ultrasound transducerassembly optionally comprises a support carrying the first and secondtransducer elements and formed to provide a cavity dimensioned toreceive the patient's head. The transducer elements may be uniformlydistributed on the support.

Another example aspect provides a controller for a drug delivery system.The controller comprises a data processor configured to: register apreviously-obtained image of a patient's head to an ultrasound imagethat includes one or more structures in the patient's head to yield atransformation relating coordinates in a frame of reference of thepreviously obtained image to coordinates in a frame of reference of theultrasound image, wherein the previously-obtained image includes the oneor more structures; using the transformation determining coordinates ofat least one target region in the frame of reference of the ultrasoundimage; and based on the coordinates of the at least one target regiondetermining a location for at least one ultrasound treatment transducerto deliver ultrasound energy to the at least one target region. It isnot necessary for the ultrasound image to include the target region. Theultrasound image may have a much smaller field of view than thepreviously obtained image. The controller may optionally be configuredto control a drug delivery system and/or a robotic manipulator forpositioning one or more ultrasound transducers or transducer elements.

Another example aspect provides a method for delivering a drug to atarget region within a person's brain, the method comprises: obtainingan ultrasound image of one or more structures within the person's headusing one or more imaging ultrasound transducers; registering theultrasound image to a previously acquired image of the person's head;based on the registering determining a location of the target regionrelative to the one or more imaging ultrasound transducers;administering the drug into the patient's bloodstream and controllingone or more treatment ultrasound transducers to deliver ultrasoundenergy to the target region using known positions of the treatmentultrasound transducers relative to the imaging ultrasound transducersand the location of the target region relative to the one or moreimaging ultrasound transducers.

Further aspects of the invention and features of example embodiments ofthe invention are described below and/or illustrated in the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting example embodiments are illustrated in the appendeddrawings.

FIG. 1 is a schematic illustration showing an example prior art drugdelivery system that uses MRI scanning during treatment to guide theplacement of ultrasound transducers.

FIG. 2 is a schematic illustration showing an ultrasound systemaccording to an example embodiment that is operable to deliver a drug toa patient.

FIG. 3 is a flow chart for an example method that exploits lowattenuation acoustic windows to guide ultrasound to target regions.

FIG. 4 is a schematic illustration of apparatus according to an exampleembodiment that includes showing multiple ultrasound transducers thatare configured to either only transmit, or to transmit and receiveultrasound energy.

FIG. 5 is a block diagram of apparatus according to another exampleembodiment.

FIGS. 6A-6B are schematic illustrations showing example ultrasoundtransducer elements individually and coupled together.

FIG. 7A is a schematic illustration showing an example ultrasound systemthat includes robotic arms operable to position ultrasound transducers.

FIG. 7B is a schematic illustration showing an example ultrasound systemwith transducers that are manually placed.

FIG. 8 is a schematic illustration showing an example arrangement forcoupling one or more sensors to a transducer.

FIG. 9 is a flow chart for an example method for registeringpre-operation images with ultrasound images.

FIG. 10 is a schematic illustration showing an example registrationprocess.

FIG. 11 is a flow chart for an example method for registeringpre-operation images with ultrasound images.

FIGS. 12A-12B are illustrations of how the registration process may beperformed.

FIG. 13 is a schematic illustration showing an example method fordetermining the distance from the surface of the skull to a targetregion.

FIG. 14A is a graph illustrating example waveforms of ultrasonic energythat may be transmitted and received from an element that operating inan imaging mode. FIG. 14B is a graph illustrating example waveforms ofultrasonic energy that may be transmitted by an element operating in atreatment mode.

FIGS. 15A-15B are flow charts for example methods that employ the use ofdifferent types of microbubbles for imaging and for facilitatingtreatment.

FIG. 16 is a schematic illustration showing how standing waves may bereduced or eliminated.

FIG. 17 is a schematic illustration showing how the same subset ofelements may be used for different scanning planes.

FIG. 18 illustrates one configuration of a user interface that a usermay use to interact with an ultrasound system.

DETAILED DESCRIPTION

Throughout the following description, specific details are set forth inorder to provide a more thorough understanding of the invention.However, the invention may be practiced without these particulars. Inother instances, well known elements have not been shown or described indetail to avoid unnecessarily obscuring the invention. Accordingly, thespecification and drawings are to be regarded in an illustrative, ratherthan a restrictive sense.

Some aspects of this invention provide systems and methods which useultrasound to produce one or more ultrasound images of a part of apatient's head. These one or more images may be registered withpreviously acquired images by identifying one or more structures thatare present in both the ultrasound images and the previously acquiredimages (“common structures”). The registered images may then be usedlocate one or more target regions relative to transducers used toacquire the ultrasound image(s). The target regions may have knownlocations relative to the common structures. Ultrasound may then bedelivered to the target region(s) to open the blood-brain barrier toallow drugs to enter brain tissue. Delivery of the ultrasound to thetarget region(s) may be coordinated with injection of one or more drugsinto the patient's circulatory system. The ultrasound energy may befocused onto the target regions such that the blood brain barrier isopened selectively in the target regions.

Methods and apparatus as described herein may optionally andbeneficially apply two or more ultrasound transducers. One or more ofthe transducers is operable for acquiring images of structures in thepatient's head including parts of the brain (“imaging transducers”). Oneor more of the transducers is operable to deliver ultrasonic energy topromote the selective opening of the blood-brain barrier in targetregions (“treatment transducers”).

Imaging the brain with ultrasound or transmitting ultrasonic energy intothe brain is a challenge because the skull attenuates ultrasound energy.Certain embodiments of the present invention exploit the fact that theskull has some areas where the attenuation of ultrasound is lower thanin other areas of the skull. These areas include, but are not limitedto, the temples of the head near the ears and behind the eyes and in theback of the head. The skull in these areas tends to be thinner comparedto the rest of the skull. Thus, ultrasonic energy can pass more easilythrough these areas compared to other areas of the skull. The areaswhere the attenuation of ultrasound is lower compared to the rest of theskull are referred to herein as “low attenuation acoustic windows”.Ultrasound energy may be transmitted into the brain via low attenuationacoustic windows and/or echo signals may be received from structureswithin the brain via low attenuation acoustic windows more easily thanvia other areas of the skull.

Ultrasound imaging relies on the transmission of ultrasound energy intothe patient's body, and subsequently, detecting the energy that isreflected by internal tissue. Regions in the head that can be imaged byultrasound are limited, as there are few low attenuation acousticwindows in the skull. Even through these low attenuation acousticwindows, the structures that can be effectively imaged are limited.

Diagnostic imaging is often conducted when diagnosing a patient forbrain tumors. As such, brain images acquired using other modalities,such as MRI or computed tomography (CT), are available for manypatients. MRI and CT do not suffer from the same penetration issuesthrough the skull as ultrasound imaging. MRI scans of the brain aretherefore able to image the entire brain, including the samestructure(s) that may be imaged with an ultrasound transducer through alow attenuation acoustic window. Various implementations of the presentinvention apply the realization that the same structure(s) may be imagedwith two different imaging modalities.

Certain structures may be imaged by ultrasound imaging performed througha low attenuation acoustic window such as one or both temples. Thesestructures may include, for example, structures of the brain such as thecircle of Willis, ventricles, and the corpus callosum and/or otherstructures in known positions relative to the patient's brain (e.g.dental implants, surgical screws, orthopaedic hardware affixed to thepatient's skull or the like). All or parts of these same structures maybe visible in a pre-operation MRI or CT scan. In some embodiments of theinvention, ultrasound images obtained by one or more imaging ultrasoundtransducers via low attenuation acoustic windows are “registered” to MRIor CT images obtained of the same patient. Registration may be performedby processing the images of common structure(s) imaged in both imagingmodalities.

Regions where ultrasound energy is to be delivered to facilitatetreatment (“target regions”) generally have known locations in pre-opimages (e.g. MRI and/or CT scans). The location of a target region maybe found in a coordinate system of the presently obtained ultrasoundimage through the process of registration. It is not necessary for thetarget region(s) to be in the field of view of the ultrasound image.Ultrasound energy may then be delivered to the target region(s) usingone or more treatment ultrasound transducers or transducer elements thathave known position(s) and orientation(s) relative to the ultrasoundimage.

The known position(s) and orientation(s) of the treatment transducer(s)and the imaging transducer(s) may be maintained by any one or more of:mounting the treatment transducers and imaging transducers used toobtain the ultrasound image to a common fixed support structure;mounting the treatment transducers and the imaging transducers to asupport structure (e.g. an articulated arm or other manipulator) havingone or more joints that are movable and tracking positions of thejoint(s); manually positioning the treatment transducers and imagingtransducers by an operator; and using a position tracking system (e.g.an electromagnetic position tracker) to monitor relative positions andorientations of the treatment transducer(s) and the imagingtransducer(s). Example implementations which exploit these approachesare described herein.

FIG. 2 shows an example system 200 that may be used for imaging at leasta portion of a patient P's brain and subsequently delivering ultrasoundto selectively open patient P's blood-brain barrier. System 200 does notrequire use of an MRI scanner during treatment (the “intra-op period”).System 200 includes an ultrasound system 210. Ultrasound system 210 iscoupled to ultrasound transducer assembly 220 via transducer cable 225.Ultrasound transducer assembly 220 is shown to be in the shape of ahelmet having a concave opening dimensioned to receive at least the toppart of a patient's head. Other configurations are not excluded.Ultrasound transducer assembly 220 may comprise one or more imagingtransducers and/or treatment transducer elements.

The illustrated system 200 includes an electronically controlledintravenous (IV) drug delivery system 230. In this non-limiting example,IV system 230 is shown to include one IV bag 235 and an electronic valveor valve system 240. In other embodiments, IV system 230 may comprisemultiple bags 235. Electronic valve 240 may be used to control the rateof flow of the contents of the one or more bags in IV system 230.Electronic valve 240 may be controlled by ultrasound system 210 whichmay send control signals via control line 245. Signal interconnectmodule 250 may send and receive signals from external and peripheraldevices, such as electronic valve 240, and communicate with aperipherals and I/O module within ultrasound system 210 as will bediscussed later. Signal interconnect module 250 may also include theability to connect and disconnect cables that connect to externaldevices and peripherals.

Overview

FIG. 3 is a flowchart showing a non-limiting example method 300 that maybe performed to determine the position(s) and orientation(s) for one ormore treatment transducers that may be configured to deliver ultrasoundin conjunction with treating a patient. At step 305, pre-op CT or MRIimages are imported into a system 200. System 200 may be applied forimaging at least a portion of a patient brain and subsequentlydelivering ultrasound to selectively open the patient's blood-brainbarrier. In the illustrated embodiment ultrasound system 210 includes acontroller that provides overall control over system 200 and the pre-opimages are provided in or imported into a data store accessible byultrasound system 210.

Step 310 performs ultrasound imaging to obtain images of certain targetstructures (e.g. circle of Willis). The imaging may be performed inreal-time and monitored by a human operator. This may beneficially bedone by placing imaging transducer(s) to obtain the ultrasound imagesthrough low attenuation acoustic windows in the patient's skull.

Step 310 also identifies common structures that may be used forregistration. Step 320 registers the ultrasound image and the pre-opimage by comparing the position and orientation of the commonstructure(s) in the ultrasound image to the position and orientation ofthe same common structure visible in the pre-op images. The registrationyields a transformation by which coordinates of points in the pre-opimages may be transformed to yield coordinates of the same points in aframe of reference of the ultrasound image or vice versa.

At step 325, target regions where ultrasound is to be delivered areidentified. Target regions may be selected in the pre-op image. Step 325may comprise, for example, identifying a tumor or other diseased arearequiring treatment, or an area of the blood-brain barrier to be opened.This selection may occur at any time after the pre-op image(s) areobtained. In some cases one or more target regions are identifiedoutside of system 200, for example using treatment planning software. Insuch cases data identifying the target region(s) may be imported intosystem 200 in step 305.

The current desired coordinates to which ultrasound energy should bedelivered by one or more treatment transducers will be known onceregistration has occurred and the target region is selected. Theposition(s) and orientation(s) of the one or more treatment transducersmay then be calculated at step 330. Step 330 may comprise, for example,determining desired coordinates at which one or more treatmenttransducers should be placed and/or selection from among a plurality oftransducers or transducer elements of transducers and/or transducerelements to be used to deliver ultrasound energy to a specific targetregion. Method 300 may be performed, for example, with any of theultrasound system configurations discussed below.

Ultrasound System Apparatus

FIG. 4 shows an example ultrasound transducer assembly 220 which may beplaced over patient P's head. Ultrasound transducer assembly 220includes a support structure 405 that holds and positions pluraltransducer elements in desired locations on the patient's head. Theportion of patient P's head 410 that is behind ultrasound transducerassembly 220 is shown in bold dashed lines.

Ultrasound transducer assembly 220 comprises transducer elements 415.Optionally, elements 415 include imaging elements 415A that are adaptedfor imaging, and treatment elements 415B that are adapted for deliveringultrasound to facilitate treatment.

Groups of elements 415, or subsets, may be configured to perform acommon function such as imaging the brain or delivering ultrasound tofacilitate treatment (e.g. by opening the blood-brain barrier). In FIG.4 , some imaging elements 415A are included in each of subsets 420A and420B. Some treatment elements 415B are included in each of subsets 425Aand 4256.

Elements 415A and 415B may differ from one another in various waysincluding one or more of:

-   -   location (e.g. imaging elements 415A may be clustered or        concentrated near one or more low attenuation acoustic windows        while elements 4156 may be more widely distributed—in cases        where the approximate location of one or more target regions is        known in advance transducer assembly 220 may optionally be        customized by concentrating elements 415B in areas suitable for        delivering ultrasound energy to the target region(s));    -   connection to receiving circuits (e.g. imaging elements 415A are        connected to receiving circuits which may detect ultrasound        echoes while treatment elements 415B are optionally not        connected to receive circuits);    -   connection to different transmitting circuits (e.g. treatment        elements and imaging elements may be driven by differently        designed driving circuits. The treatment elements may, for        example, be driven by higher-power driving circuits optimized to        operate at lower frequencies than the imaging elements);    -   power (e.g. treatment elements 415B may be constructed to        generate higher power ultrasound than imaging elements 415A);    -   optimum operating frequency (e.g. treatment elements 415B may        operate most efficiently at lower frequencies than imaging        elements 415A);    -   size (e.g. treatment elements 415B may be larger and/or more        widely spaced apart than imaging elements 415A);    -   configuration (e.g. treatment elements 415B may include acoustic        lenses that focus at different depth(s) than imaging elements        415A).

Imaging elements 415A may be located at positions in transducer assembly220 that are adjacent to low attenuation acoustic windows whenultrasound transducer assembly 220 is worn by patient P. This isillustrated by subsets 420A and 420B in FIG. 4 being located at thetemples. Subsets of transducer elements that are configured to produceimages may generally be referred to as “imaging subsets”.

Subsets of transducer elements that are used to deliver ultrasoundenergy to facilitate treatment do not have to be situated near a lowattenuation acoustic window. As such, “treatment subsets” may beselected to include those treatment elements at locations from which itis optimal to deliver ultrasound to a target region. Treatment subsetswill often be at different locations from imaging subsets. This isillustrated by subsets 425A and 425B. In some embodiments transducer 220includes a large number of treatment elements located at a wide range ofpositions from which ultrasound energy may be delivered to a wide rangeof target regions. From this large number of treatment elements a subsetmay be chosen to deliver ultrasound energy to specific target region(s).

Subsets of transducer elements include enough elements to accomplishtheir task, be it imaging or delivering ultrasound energy thatfacilitates treatment. The organization of the elements within a subsetmay also be a factor for effective operation. In FIG. 4 , subsets 420A,420B, 425A, and 425B are pictured to be circular, with the individualelements organized in a 2D array. However, element groupings within asubset need not be circular in nature. They may be of any appropriateshape such as a curved-linear format. In an example embodiment, thepreferred size of a subset is in the range of 2 to 3 cm in diameter.Individual transducer elements 415 may have a range of shapes. Eachelement may have a circular cross section, although other shapes such asrectangular shapes are not excluded.

Different subsets may differ from one another in various ways including,the number of transducer elements included in the subset, the shape andsize of the area over which the included transducer elements aredistributed and the way in which the transducer elements are operated toperform a desired function (e.g. imaging or delivering ultrasound tofacilitate treatment).

Ultrasound Control Subsystems

FIG. 5 illustrates the operation of a control subsystem of an ultrasoundsystem 210 operable to image and deliver treatment to a patient's brain.Control subsystems as described herein may be applied to ultrasoundsystems having other configurations and/or supplied as stand-alonecomponents. Block 505 comprises a data store that may contain imagesfrom other modalities (e.g. MRI or CT scans), as well as other data.Block 505 is in communication with control and computation block 510,which may include one or more modules. The modules within control andcomputation block 510 may be employed either individually, or in anycombination or sub-combination with each other.

Module 510A generates control signals that affect operation oftransducer elements that will be used for a transmit operation (i.e.where an element sends ultrasonic energy into the brain).

For example, block 510A may generate control signals that determine oneor more of:

-   -   what transducer elements 415 or subset comprising transducer        elements 415 will be used for a transmit operation;    -   what waveform(s) will be transmitted by transducer elements 415;    -   what transmit delays will be applied to individual transducer        elements 415;    -   at what amplitude(s) will individual transducer elements 415 be        driven;    -   what transmit apodization function will be applied to transducer        elements 415;    -   at what time(s) will transducer elements 415 be operated to        transmit ultrasound;    -   at what frequency(ies) will transducer elements 415 be driven;    -   etc.

Module 510A may include or have access to a data structure thatindicates the locations of transducer elements 415. This data structuremay be used in determination of what transducer elements 415 use for aparticular transmit operation and/or to calculate transmit delays, forexample.

Module 5106 generates control signals that affect operation oftransducer elements that will be used for a receive operation (i.e.where an element receives echo signals from structures within thebrain). Control signals from module 5106 may determine, for example, oneor more of:

-   -   what transducer elements 415 are used to receive;    -   beamforming parameters;    -   receive apodization function;    -   receive gain;    -   receive depth;    -   image processing to be applied;    -   etc.

Storage module 510C includes a data store that may be used to storevarious information including, but not limited to, digitizedradio-frequency (RF) data received at the elements that are configuredto receive, images acquired from other modalities and transferred toultrasound system 210, and intermediate or final results of computationsperformed within control and computation block 510.

Module 510D may perform computations related to image formation andimage processing. Module 510D may apply any suitable technology forultrasound image formation. In a non-limiting example of a computationrelated to image formation, RF data received from some or all imagingelements 415A may be summed in module 510D based on receive delayscomputed by module 510B. Images of the anatomy may be formed based onthese sums. In a non-limiting example of a computation related to imageprocessing, after the images are formed, they may be processed invarious ways including, but not limited to, filtering, log compression,mapping to post-processing maps, etc.

Module 510E may perform various computations such as, but not limitedto, computations with respect to registration of intra-op ultrasoundimages to images from other imaging modalities. The results of thesecomputations may be applied to select and/or position transducersoperable to transmit the appropriate energy.

Module 510F may generate and provide control signals for variousprocesses such as, but not limited to, real-time imaging, and thecoordination of timing of an intravenous injection of drug or othercompound into a patient with the timing of transmission of ultrasoundenergy to a patient.

Peripheral controls and I/O module 510G may generate control signalsthat may be sent to external devices and peripherals that may be used inconjunction with ultrasound system 210. These devices and peripheralsmay include without limitation, an intravenous drug delivery system,transducer positioning systems, transducer position detecting systems,etc. I/O module 510G may also accept inputs from external devices andperipherals and provide them to other modules within control andcomputation block 510.

Control and Computation block 510 may also interface to user interfacemodule 515. User interface module 515 may allow the use of one or moreuser interface devices such as, but not limited to, a keyboard, mouse,touch screen, trackball, touch pad, gesture-based interface, voicecommand interface, discrete switches or controls, and a display 520.Through the user interface, authorized users may operate ultrasoundsystem 210. These operations may include the ability to choose thetarget region and to choose the subsets of elements 4156 to be used togenerate ultrasound for treatment (if a manual control option isselected). Other operations may also be possible. In some embodimentsselection of the target region is done by allowing a user to navigate a3D rendered image using one or more of the user interface devices.Display 520 may be used to display various information including, butnot limited to, the obtained ultrasound images, images from othermodalities, merged images, patient information, and instructions oroptions for an authorized user.

For example, after having determined the subset(s) of transducerelements 415 that are to transmit ultrasonic energy, parameters may beset for a transmit operation. These parameters may include, but are notlimited to, length of delays and transmission frequency. Theseparameters may be selected manually by the operator, or automaticallybased on a set of parameters, as discussed elsewhere herein. Theseparameters may be used and applied to various modules of ultrasoundsystem 210.

During a transmit operation, system controls module 510F may send theappropriate control signals based on the parameters to transmit (TX)Amplifier 430. TX Amplifier 430 may then apply the appropriate signal toelements of ultrasound transducer assembly 220 either directly throughmultiplexer (MUX) 435 or through transmit/receive (TX/RX) switch 440 andthen through MUX 435. In FIG. 5 , TX amplifier 430 is shown to becoupled to MUX 435 by dotted line 525 and coupled to TX/RX switch bydashed line 530. This configuration enables the ultrasound system todrive transmit only elements in addition to the elements that areconnected to both transmit and receive. The operation of differentelement types in this manner provides for certain advantages that areexplained elsewhere herein.

In contrast, in conventional ultrasound imaging systems, a TX amplifieris typically only coupled to a TX/RX switch (with subsequent connectionsto the elements possibly through a MUX) and only support elements thatcan both transmit and receive. Thus, as dotted line 525 illustrates, TXamplifier 430 couples to MUX 435 which then couples via connection 225Cto an example of a transmit only element 415B. Simultaneously, TXamplifier 430 may couple to TX/RX switch 440, which then couples throughMUX 435 to connect through connection 225A to an example transmit andreceive element 415A. Connection 525 from TX amplifier 430 to MUX 435 asshown in FIG. 5 is not present in conventional ultrasound imagingsystems.

TX/RX switch 440 may serve to protect electronics in the receive pathfrom relatively high voltages that may be present in the transmit path.Protection for elements that transmit and receive may be required as theelectronics that transmit and the electronics that receive areelectrically connected to the same physical transducer element. In theexample embodiment shown in FIG. 5 , the TX/RX switch 440 is not neededfor transmit only element 4156 as element 4156 is not used for thereceive operation.

In some embodiments, MUX 435 may be provided where the number ofelements in ultrasound transducer assembly 220 is larger than the numberof electronic channels within ultrasound system 210. With MUX 435,various subsets of elements in ultrasound transducer assembly 220 may beoperated with the appropriate parameters even where there are fewerelectronic channels than there are elements. It is anticipated that inpractice, when utilizing these system and methods, that ultrasoundtransducer assembly 220 would have more elements of each kind (e.g.imaging elements 415A and treatment elements 415B) than channels capableof operating each kind.

For a receive operation, MUX 435 connects the elements that transmit andreceive to the receive side electronics. The receive signal path isshown by the arrows going right starting from example transmit andreceive element 415A. In this example embodiment, the signal passesthrough MUX 435, TX/RX switch 440, low noise amplifier (LNA) 445,time-gain compensator (TGC) 450, and analog to digital convert (ADC)455. Signals digitized by ADC 455 may then be stored in storage module510C for further processing by control and computation block 510.

FIG. 4 , illustrates configuration of the general control subsystem ofFIG. 5 for different transducer elements. Imaging element 415A iscoupled to electronics 429A that enable transmit and receive operationsas discussed above. TX amplifier 430A is coupled to TX/RX switch 440Awhich is then coupled to MUX 435A before coupling to element 415Athrough cable 225A, as shown by the dashed arrows. For receiveoperations, the ultrasound signal passes through MUX 435A, TX/RX switch440A, LNA 445A, TGC 450A, and ADC 455A, as shown by solid arrows. Theoperation of both transmit and receive functions allows ultrasoundimaging to be performed by ultrasound system 210. Electronics 429B isconfigured for another imaging element 415A opposite to the setdescribed above. Electronics 429B may be the same as or similar toelectronics 429A. The components included in electronics 429B areidentified by references that include the suffix ‘B’.

Element 415B is an example of an element that is configured to deliverultrasound energy to facilitate treatment. In this example, element 415Bis configured to only deliver ultrasound to target regions. Element 415Bdoes not require electronics to enable it to receive echo signals.Therefore, element 415B is shown to be coupled to electronic components429C that only enable transmit operations. Here, TX amplifier 430C iscoupled directly to MUX 435C which is then coupled via cable 225C(illustrated by dotted arrows) to element 415B. A set of electronics429D similar to electronics 429C is configured for another treatmentelement 415B. The components included in electronics 429D are identifiedby references that include the suffix ‘D’.

Forming subsets of elements which may be configured so that all elementsin a subset perform the same operation of either transmit only ortransmit and receive may be advantageous. In FIG. 4 , all elementswithin subsets 420A and 420B may be configured to transmit and receive,while all other elements, such as those in subsets 425A and 425B, may beconfigured to transmit only. An advantage that is offered by thisapproach is that certain subsets may be configured to optimally transmitand receive to form images, while other subsets may be configured tooptimally only transmit to promote opening the blood-brain barrier. Insome embodiments, the elements in the various subsets may be operatedwith different parameters such as, but not limited to, transmitfrequency, and transmit bandwidth.

Elements in these various subsets may be designed differently and behavedifferently. Relatively higher ultrasound frequencies have been shown toexperience lower amounts of attenuation and be effective for imagingcertain portions of the brain. As such, in a non-limiting example,subsets of elements that form images may have a higher frequencyresponse (e.g. centered at 2 MHz). In contrast, relatively lowerultrasound frequencies applied to the brain can selectively increase thepermeability of the blood-brain barrier. As such, in a non-limitingexample, subsets of elements used to deliver ultrasound energy tofacilitate treatment may have a lower frequency response (e.g. centeredat 0.5 MHz). In some implementations treatment elements are driven atfrequencies in the range of 0.25 MHz to 5 MHz. In some implementationsimaging transducer elements are driven at frequencies in a frequencyrange of about 1.75 MHz to 10 MHz.

In the example shown in FIG. 4 and in certain other example embodimentsof this invention, the operation of one or more transducer elements thatcan transmit and receive, along with the operation of one or moretransducer elements that can only transmit, is advantageous. Suchconfigurations allow more transducer elements to be supported by fewerelectronic circuits. As an example, transmit only elements require lesselectronics. Although it is desirable to have transmit only elementsalong with elements that transmit and receive, the systems and methodsdescribed herein do not preclude other configurations. In someembodiments, the same element can be operated in a “transmit only” mode,with one set of parameters when delivering ultrasound energy tofacilitate treatment as well as in a “transmit and receive” mode, withanother set of parameters when imaging.

FIGS. 6A and 6B illustrate an example embodiment in which one or moreelements are coupled to one or more sensors such as, but not limited to,angle sensors, pressure sensors, thermal sensors, proximity sensors,electroencephalogram (EEG) sensors, and slippage sensors. Such sensorsmay be provided optionally and beneficially in ultrasound transducerassembly 220.

In FIG. 6A, element group 600 comprises two ultrasonic elements 415,which are mounted on a common mechanical sub-structure 605. Theorientation of mechanical substructure 605 may be controlled by any ofvarious mechanisms. In this example embodiment, the orientation ofmechanical sub-structure 605 is controlled by linear actuatorscomprising motors 610 (e.g. stepper motors, servo motors) or otherlinear actuators, only one of which is labelled for clarity. Each motor610 may be coupled to a lead screw 615, only one of which is labelled,whose position may be controlled by a corresponding motor 610. Thus, bycontrolling the position of each lead screw 615 independently, theorientation of elements 415 may be controlled. Other implementations mayuse other types of linear actuators.

Sensors 620 and 625 are also shown. In the illustrated embodimentsensors 620 and 625 are embedded within cover 630, which may allowultrasonic energy to pass through it. Cover 630 may also serve toseparate the elements and skin, protecting each one from the other. Insome embodiments, one or more of sensors 620 and 625 may be used tomeasure and report the orientation of the group of elements back to theultrasound system. In these and other embodiments other sensedparameters may optionally be reported back to the ultrasound system. Inthis example embodiment, two sensors are shown, but more or fewersensors may be provided.

FIG. 6A shows that the four motors 610 (e.g. stepper motors, servomotors or other rotary actuators) are coupled to mechanical structure635. Mechanical structure 635 may provide the structure of ultrasoundtransducer assembly 220. FIG. 6B shows a case where three instances ofelement group 600 are coupled to mechanical structure 635, which formsor is a part of ultrasound transducer assembly 220. Electricalconnections to the elements and the sensors are not illustrated in thefigures for the sake of clarity. The spatial position of element group600 within the structure of ultrasound transducer assembly 220 may beknown to the ultrasound system from outputs of sensors attached to eachelement group 600 and/or from known locations of the transducer elementsincluded in element group 600.

The capability to measure and control the orientation of elements withinultrasound transducer assembly 220 is advantageous as it facilitatesorienting elements in desired configurations, such as normal or nearlynormal to the surface of the skull. This orientation is known to reduceor remove the possibility of mode conversion between longitudinal andshear waves at the surface of the skull. In some embodiments, theorientation of elements may be adjusted automatically. A pre-op imagemay be used to assess the angularity of the skull (e.g. by determining atangent plane) at any location, and through the process of registration,as discussed herein the angularity of any section of the skull may beknown. An element may thus be automatically adjusted to be oriented at adesired angle with respect to the skull using this knowledge.

This capability is also advantageous because it permits ultrasoundtransducer assembly 220 to accommodate differently shaped heads. In someembodiments, motor 610 may advance or retract one or more lead screws615 to position one or more ultrasound elements 415 or element groups600 such that ultrasound transducer assembly 220 conforms to the shapeof a patient's head. It will be appreciated that motor 610 can be anytype of linear actuator operable to advance or retract element(s) 415,such as a stepper or servo motor.

Robotically Positioned Transducers

FIG. 7A shows an ultrasound system 700 according to an exampleembodiment which features a robotic manipulator (in this exampleprovided by electromechanical arms). In system 700, ultrasonic elementsare in element housings 705A, 705B and 705C (any individual elementhousing herein referred to as element housing 705, or collectively aselement housings 705). Element housing 705 and the elements containedwithin it may collectively be called a transducer 710.

Each transducer 710 can include one or more transducer elements. Theelements can be arranged in any of various configurations such as, butnot limited to, linear, in a 2D array format, randomly distributed, in aplane, in a 1D convex or concave shape or in a 2D convex or concaveshape. The elements may be built on a structure that makes it possibleto attain flexible shapes of the surface of the elements. One benefit ofsuch a capability is that it may be possible to match or closely matchthe surface of the skull over the region of a footprint of the housingthat is in contact with the skull. This capability may be achieved, forexample, with mechanisms as shown in FIGS. 6A and 6B. Transducer 710 maycomprise one or more element groups 600, and may implement methods forpositioning the elements as described above.

Elements supported by element housing 705 may all be capable oftransmitting and receiving, or may only be connected for transmitting.It is also possible for both types of elements to be present withinelement housing 705.

Each transducer 710 may be coupled to an electromechanical arm 715 orother movable support that is capable of positioning the correspondinghousing 705 in one or more degrees-of-freedom (DOFs). In someembodiments, arms 715 are capable of positioning the correspondingtransducers 710 in 6 DOFs. Arms 715A, 715B, and 715C (any individual armherein referred to as arm 715, or collectively as arms 715). It is to benoted that although three arms are illustrated, configurations with moreor fewer arms 715 are possible. In addition to being able to positiontransducer 710, arm 715 may support electrical cables or other pipes orlumens. The pipes or lumens may carry fluids such as, but not limitedto, ultrasound coupling gel. In some embodiments the pipes or lumens arearranged to dispense ultrasound coupling gel at the interface between atransduce 710 and a patient. The electrical cables, pipes, or lumensmay, for example, be carried in a conduit that extends along an arm 715.In some embodiments, the conduit is located within arm 715.

The position and orientation of each arm 715 may be manually orrobotically adjusted. In a non-limiting example, inverse kinematics maybe used to determine the angle of each joint of a mechanical arm toachieve a desired position for transducer 710. Arms 715A, 715B, and 715Care shown to be coupled to arm control units 720A, 720B, and 720Crespectively (any individual arm control unit herein referred to as armcontrol unit 720, or collectively as arm control units 720). Arm controlunits 720 may contain electrical or electromechanical systems operableto control the orientations and positions of arms 715. The details ofsuch electromechanical systems are generally well known and aretherefore not provided here.

Control signals that control the position and orientation of arms 715may originate from peripheral controls and I/O module 510G and be sentfrom ultrasound system 700 to each arm control unit 720. Cables thatcarry these control signals are illustrated by the dashed lines labeled725A, 725B and 725C. It will be appreciated that several cabling andelectronic configurations are possible, and FIG. 7A shows a non-limitingexample. In one example embodiment, MUX 435 shown in FIG. 5 may bephysically placed in ultrasound system 700. In another exampleembodiment, MUX 435 may be placed within an arm control unit 720.

Each arm control unit 720 may be coupled to a mechanical ground such as,but not limited to, a free-standing support structure, railing of beds,and support structures coupled to chemotherapy chairs. The use of amechanical ground may help provide support such that the position andorientation of arms 715 may be controlled. Just as in FIG. 2 ,ultrasound system 700 may also be coupled to an electronicallycontrolled IV drug delivery system 230.

Sensors of many types may be associated with ultrasound transducers. Forexample, such sensors may include one or more of:

-   -   one or more pressure sensors which measure forces between a        transducer and a patient;    -   one or more position sensors;    -   one or more electroencephalography sensors (EEG) to measure        electrical activity of the brain;    -   etc.

The construction of such sensors and how they may be attached totransducers is explained in further detail with reference to FIG. 8 .

Information collected from sensors may be sent via cables 725A, 725B,and 725C to control and computation block 510. Parameters such as, butnot limited to, ultrasound parameters (gain, frequency, etc.), orcontrol signals to control the position of arms 715 may be generated inresponse to the received sensor information.

In an example embodiment, a contact angle sensor in contact with thepatient's skull is coupled to a transducer 710. The sensor may reportthe angle of the head at the skull at the point of contact tocomputation block 510, which allows peripheral controls and I/O module510G to generate control signals. These control signals may be sent toarm control unit 720C and may comprise the commands necessary for armcontrol unit 720C to execute the commands and move arm 715C in such away that element housing 705C is oriented at the desired position andangle relative to the skull.

In some embodiments, once positioned at the desired configuration, arms715 may automatically reposition themselves if the patient moves. Thisautomatic repositioning may include repositioning element housings 705such that the same region of the brain may be insonated or imagedregardless of the motion of the patient.

Ultrasound system 700 may be programmed such that if the target area orvolume being insonated or imaged is different by a certain thresholdthen certain actions are triggered. In a non-limiting example, thisthreshold is triggered when a threshold proportion or amount (e.g. 1%)of the target area or volume is different from a reference target areaor volume. In some example embodiments, ultrasound images are obtainedas described herein periodically or continuously and all or somefeatures of a current ultrasound image are compared to correspondingfeatures of a previous ultrasound image. An action may be triggered if avalue of a metric indicative of differences between the current andpreviously acquired ultrasound image crosses a threshold.

The action(s) that are triggered may include, but are not limited to,stopping the imaging or treatment session, automatically trying toreposition transducer 710 so that the same area is addressed (within athreshold), or asking for an authorized human operator to intervene tomanually reposition transducer 710 (e.g. by pausing the session andproviding instructions to the operator through a user interface).

Ultrasound system 700 may include the capability of adjusting each arm715 independently of the other arms 715. Alternatively, arms 715 may beautomatically positioned in concert with one another, given informationon the shape of the patient's head and its motion.

In some embodiments, information about the patient's movements may notbe limited to those provided by the sensors within element housings 705.Sensors such as, but not limited to, cameras may also be placed in otherlocations such as the bed, ceiling, the patient, and other freestandingstructures. Such sensors may be used to supply information on patientmotion. Camera based position tracking systems are commerciallyavailable and may be applied to track position(s) and orientations oftransducer(s) 710 and/or the patient's head.

FIG. 7A shows inertial measurement unit (IMU) sensor 730 placed on thepatient's head. The reading from this sensor may be sent via cable 735to ultrasound system 700 to be processed by peripheral controls and I/Omodule 510G. If the reading of the patient motion exceeds a thresholdvalue, module 510G may calculate new positions for arms 715.

Calculations regarding change in patient position may be performedcontinually or on a periodic basis, depending on how ultrasound system700 is configured. In an example calculation, an initial position of thepatient's head, is obtained and stored along with the position andorientation of a transducer 710. Assuming that transducer 710 isinitially at an appropriate location for the function it is configuredto perform, any movement of the patient may be recorded. Thus, anychange in position of transducer 710 relative to the patient may triggera calculation to determine whether a current location of transducer 710is still within a threshold of the appropriate target volume. If athreshold is exceeded, then control signals may be sent to arm controlunits 720 to reposition element housings 705 to target the desiredvolume. Actions other than updating the position of element housings 705may also be programmed to take place. In an example embodiment, if thethreshold is exceeded by a certain amount, actions such as stoppingscanning, or providing warning messages may be performed by ultrasoundsystem 700.

Ultrasound system 700 may provide certain advantages over ultrasoundsystem 210 in some scenarios. For example, ultrasound system 700 mayrequire fewer transducer elements for operation, as transducer elementsmay be dynamically positioned during treatment. Furthermore, variationsin patients' anatomy, namely head size and shape, can make fabricationof an ultrasound transducer assembly 220 suitable for use with a rangeof patients difficult.

Manually Positioned Transducers

FIG. 7B illustrates an ultrasound system 750 having yet anotherconfiguration. Ultrasound system 750 is similar to ultrasound system 700and also comprises one or more transducers which may image and/ordeliver ultrasound energy to facilitate treatment. In system 750 one ormore, ultrasound transducers may be placed at appropriate positions on apatient's head manually by a person. In some embodiments, 6 DOF sensorsmay be coupled to transducers 760A and 760B. Such sensors may allow forthe positions and orientations of transducers 760A and 760B to betracked and communicated to ultrasound system 750. Although notillustrated, patient movements may be monitored in this configurationjust as described in FIG. 7A. In other embodiments, a single transducermay be provided which an operator could appropriately place in one ormore positions to both perform imaging and facilitate treatment.

Sensors such as position or pressure sensors may be used beneficiallywith ultrasound system 750. As an illustrative example, providingposition sensors on transducer 760B would allow ultrasound system 750 tocompare the actual location of transducer 760B to a desired location.This would allow for further feedback and instructions to be provided toa user to adjust its position.

FIG. 8 shows an example construction for coupling one or more sensors toa transducer. In this example, rigid sleeve 805 fits tightly overtransducer 810. Sleeve 805 supports one or more sensors. Sensors 815A,815B, and 815C (any individual sensor herein referred to as sensor 815,or collectively as sensors 815) may be placed on sleeve 805 as pictured,or wherever else appropriate. The rigidity of sleeve 805 allowstransducer 810 and sensors 815 to remain stationary relative to eachother once sleeve 805 is fitted over transducer 810. In this exampleembodiment, sleeve face 820 is not level with the surface of transducer810. However, the two faces may be in the same plane in otherembodiments.

A sensor, such as sensor 815C, may be a pressure sensor, measuring thepressure with which the transducer presses against the skin of apatient. As shown, transducer 810 may be electrically connected totransducer cable 825. Similarly, sensors 815 may be connected to sensorcable 830. In the present example, sensor 815C may output pressure datathrough sensor cable 830 to ultrasound system 700 or 750, which may thenbe received by control and computation block 510.

Modules within control and computation block 510 may compare thereceived pressure data to a range of desired pressures. The data on therange of desired pressures may be stored in storage module 510C. If thereceived pressure data falls outside the desired range, certain actionsmay be triggered. These actions include, but are not limited to, showinga warning through user interface 515, and if transducer 810 is coupledto an electromechanical arm 715 such as one shown in FIG. 7A, controlsmay be sent to arm control unit 720 to alter the position of transducer810 to obtain a pressure within the desire range.

Establishing a Common Frame of Reference

It may be advantageous to establish a common frame of reference todescribe measurements of location and orientation of the various sensorsin a common coordinate system. A common frame of reference is aconvenient but arbitrarily chosen coordinate system having an origin andorientation to which all images and locations can be referred. Forexample, in the configuration illustrated in FIG. 7A, a coordinatesystem 740 may be located relative to arm control unit 720A. Thiscoordinate system may then be used as a frame of reference for all otherposition and orientation related measurements (the “common frame ofreference”). In the configuration illustrated in FIG. 7B, coordinatesystem 790 may be used to establish the common frame of reference. Inboth of these examples, an origin of the frame of reference is locatedat a mechanical grounds (745 and 795, respectively). The frame ofreference in the configuration shown in FIG. 4 is represented bycoordinate system 460. This frame of reference is different from theones shown in FIGS. 7A and 7B in that it is not mechanically grounded.Coordinate system 460 can move if the patient moves his or her head.However under the assumption that ultrasound transducer assembly 220 andhead 410 are not moving relative to each other, this type of frame ofreference is equally valid and appropriate and results in no additionalcomputational complexity.

Some implementations provide systems and methods for establishing acommon frame of reference using a position sensing system. Various typesof position sensing systems may be utilized such as, but not limited to,electromagnetic (EM) based system or optical based systems.

FIGS. 7B and 8 show an example embodiment which uses an EM transmitter785 to determine positions of sensors associated with ultrasoundtransducers. For example, EM sensors may be placed on sleeve 805 andreference EM transmitter 785 may be able to establish the transducer'sposition and orientation in a coordinate system defined relative toreference EM signal generator 785. Thus, if multiple transducers werepresent (as shown in FIG. 7B), and each transducer is coupled to one ormore EM sensors, the position and orientation of each of the transducersmay be found in relation to the frame of reference, and subsequently, inrelation to each other. Knowledge of the position(s) and orientation(s)of transducers may be used optionally and beneficially with the methodsof placing transducers in an appropriate location as discussed above.

Obtaining Ultrasound Images

Returning to example method 300 in FIG. 3 , after pre-op MRI or CTimages of the head are obtained and imported into an ultrasound systemin step 305, real time imaging of at least a portion of the patient'shead is performed in step 310. It is desirable to obtain an image ofparts of the patient's brain which include certain structures within thebrain. As described previously, certain structures may be imaged throughlow attenuation acoustic windows using ultrasound. As such, in someembodiments, ultrasound transducers used to form images may bepositioned at these low attenuation acoustic windows. Ultrasound imagingmay then be performed, and structures visible in these images may beselected to serve as the ultrasound image reference region. The processof selection may be accomplished by segmentation as explained below.

To illustrate how this may be performed with the configuration in FIG. 4, ultrasound transducer assembly 220 may be positioned on patient P'shead such that subsets 420A and/or 420B are adjacent to patient P'stemples. Using the knowledge about the general anatomy of the skull,ultrasound transducer assembly 220 may be constructed such that when apatient wears the assembly, subsets configured to image are positionedadjacent to one or more low attenuation acoustic windows.

In the configuration shown in FIG. 7A, instructions may be provided byultrasound system 700 to control arms 715 such that imaging transducer710A and/or 710B are positioned adjacent to low attenuation acousticwindows.

In the configuration shown in FIG. 7B, a human operator may manuallyposition transducer 760A such that it is placed appropriately at one ofthese windows. Sensors on transducer 760A may detect whether the desiredlocation has been reached and may give feedback to the operator ifadjustments are required.

Reference Region Selection

In step 315, the image of the structure seen in the ultrasound imagereference region obtained in step 310 may be identified in the pre-op MRor CT scan. As an example, this may involve a human operator selectingthis structure in a slice of the pre-op image dataset or in a 3D modelconstructed from the pre-op image dataset. Again, this selection may beaccomplished by segmentation. The region in both the pre-op image(s) andthe ultrasound image containing the common structure will becollectively referred to as “reference regions”. In some embodiments,reference regions may comprise one or more of the following structures:the circle of Willis, ventricles, and/or the corpus callosum. Utilizingthe common structure identified in step 315, the images of theultrasound scan can be registered to the pre-op MRI or CT scan in step320.

Registration

The registration process may use one or more features of the referenceregions. As an example, registration may be performed by matching theshape of the reference region in both the ultrasound and the pre-opmodality. Other characteristics may be used, such as the orientation ofthe reference region relative to an expected orientation, or if two ormore reference regions exist, the relative orientation of the two ormore reference regions etc. As an example, the circle of Willistypically has a distinctive shape that generally appears as an irregularhexagon or a rough circle in an ultrasound image. However, regardless ofthe shape, because the same anatomy is imaged by the two modalities, astrong correlation may exist between the images of the reference regionsin the two modalities.

FIG. 9 illustrates an example method for accomplishing the registrationin step 320. At step 320A, a common frame of reference may be chosen byestablishing a coordinate system as described above. In step 320B, thestructures of the ultrasound images may be located within the selectedcoordinate system. The distance of the imaged structure from thetransducer may be calculated based on the travel time of ultrasoundechoes and the location and orientation of the transducer are known,which allows for step 320B to be accomplished. Step 320C involvesplacing the pre-op MR or CT scan in the coordinate frame by using thesame reference regions present in the ultrasound and the pre-op images.

FIG. 10 illustrates an example registration process. Coordinate system1000 may be selected in step 320A. Coordinate system 1000 may bearbitrarily chosen to be coupled to a mechanical ground, such as armcontrol unit 720A. Ultrasound image 1005 is represented by dashed linesat a location and orientation relative to imaging transducer 1010. Thisserves to illustrate the relationship between ultrasound image 1005 andimaging transducer 1010 that created the image. As shown,P1(X1,Y1,Z1,α1,β1,ϕ1) may represent the location and orientation of theorigin of ultrasound image 1005 and may also represent location andorientation of the center of imaging transducer 1010's face oftransducer elements. Variables x, y and z may indicate the coordinateswithin coordinate system 1000 while variables α, β, and ϕ may indicatethe roll, pitch and yaw within coordinate system 1000. Step 320B maythen be completed by placing ultrasound image 1005 within coordinatesystem 1000, with its origin at P1(X1,Y1,Z1,α1,β1,ϕ1). The variablesX1,Y1,Z1,α1,β1,ϕ1 may be known from outputs of sensors such as EMsensors of an EM position sensing system that are coupled to thetransducer and the accompanying EM transmitter.

Although FIG. 10 illustrates the use of a transducer (e.g. as an elementhousing and the elements contained within), other configurations are notexcluded. For example, these methods may be performed with ultrasoundtransducer assembly 220 as pictured in FIG. 4 , where imaging transducer1010 may comprise several elements, or subsets of elements, togetherconfigured to form images (e.g. subset 420A).

A reference region, pictured by 1015 in FIG. 10 , such as the circle ofWillis, may be imaged by imaging transducer 1010 through a lowattenuation acoustic window. Step 320C of method 320 may be performed inthis example embodiment by placing the pre-op images, represented by thevolume 1020, within coordinate system 1000. Software for registrationstep 320C may be implemented utilizing registration module 510E.

FIG. 11 is a flow chart illustrating an example method which includesfurther actions that may be taken to perform step 320C to place pre-opimages into the reference coordinate system. At step 320C1, assumingthat live imaging of the patient is being performed with an ultrasoundimaging system, the live ultrasound imaging may be stopped and anappropriate frame containing the image of the reference region isselected. Following this, it is desirable to find an appropriate slicewithin the pre-op images that best corresponds to the image of thereference region in the selected ultrasound frame is selected.

FIGS. 12A and 12B illustrate an example registration process using areference region. Slices 1205 through the skull depict one set of slicesthrough the image data set acquired by the pre-op modality. Forreference, slices 1205 may represent volume 1020 in FIG. 10 . Dashedlines 1210 represent the boundary of an ultrasound image and maycorrespond to ultrasound image 1020 in FIG. 10 . It should be noted thatother slices of the pre-op images and other orientations of theultrasound plane may be obtained, and the example shown is only onepossible configuration. Reference region 1215 is represented in thisexample by an oval in the patient's brain, and may correspond to 1015 inFIG. 10 .

At step 320C2 of method 320C, an initial test frame is selected in thepre-op image(s) that closely matches the ultrasound image. An example ofsuch a test frame is illustrated by plane 1220 in FIG. 12B (shown inbold dotted lines). The selection of plane 1220 may be performedautomatically or may be guided by a human. An image may be reconstructedalong plane 1220 from the pre-op image data contained in slices 1205. InFIG. 12B, the image that is constructed would be in a planesubstantially normal to slices 1205. However, it is noted that testframes that provide for a constructed image in any number oforientations relative to slices 1205 may be selected.

Method 320C continues to step 320C3 where the correlation between theimage produced in step 320C2 and the ultrasound image frame along plane1210 produced in step 320C1 is found. In step 320C4, the correlationbetween the selected ultrasound image and the reconstructed image alongthe selected slices 1205 is found for a range of orientation angles ofthe test frame and scale factors. This process may be carried outautomatically by a computer, but may also be guided by a human in orderto converge on a solution in a more expedient manner. After a desirednumber of permutations of the various transformations are computed,method 320C continues to decision block 320C5. If all of the correlationvalues are below a desired threshold, method 320C continues to step320C6 where the location of plane 1220 is modified, and steps320C2-320C5 are repeated. Conversely, if the correlation values for anyof the calculations are above a desired threshold, decision block 320C5continues to step 320C7. Step 320C7 attempts to find a slice with aneven higher correlation value.

Using the example method 320C allows for a “best fit” slice to be found.A best-fit slice may be described as a slice of the pre-op images thatshows the same structures as seen by the ultrasound image in the sameplane and lies closest to the ultrasound image plane. For example, inFIG. 12B, the best-fit slice lies along ultrasound plane 1210. Havingcompleted the registration process in method 300 and obtained thebest-fit slice, images from the pre-op imaging modality may be locatedwithin the reference coordinate system alongside presently obtainedultrasound images. Because the coordinates of the ultrasound image'sreference region is known within the coordinate system, the best-fitslice in the pre-op images may be assigned these same coordinates. Thecoordinates of a region identified in one modality can now be found inthe other modality. This allows for a target target region identified inthe pre-op modality to be located in the ultrasound image and commoncoordinate system.

In the process of alignment in step 320C, operations such as scaling,rotation and transformation may be performed on the pre-op images. Theneed for these operations may arise due to the nature of the imagingmodalities and how the images are acquired. It is also possible thatthese operations are done on a section by section basis (i.e. each imagemay be broken down into different sections and a different set ofoperations may be used on each section). In a non-limiting example toillustrate how scaling may be performed, the selected ultrasound framein step 320C1 and the test frame from the pre-op modality in step 320C2may contain a different number of pixels. 1 cm² in the ultrasound systemmay contain 50 pixels, while 1 cm² in an MR image may contain 60 pixels.In this example, the MR image may be downsampled such that both imageshave the same pixel density. In other embodiments, the ultrasound imagemay be upsampled or downsampled to conform to a pre-op image's pixeldensity.

In some embodiments, ultrasound images and pre-op images may beprocessed. Processing may include, but is not limited to, imagesmoothing, speckle reduction, and edge detection. This processing may beperformed optionally but beneficially prior to or during registrationstep 320. Performing these steps to improve image quality may improvethe ability to find a best-fit slice. Individual characteristics fromeach imaging modality may be reduced or removed such that the imagesfrom the various modalities may be better compared or utilized inalgorithms, for example, to find correlations.

In some embodiments, the registration step is carried out plural timesusing ultrasound images obtained from different low attenuation acousticwindows. Example embodiments of this invention have thus far shownultrasound transducers or transducer elements situated at the temples toperform imaging. However, the skull is also thinner in areas such as thebehind the eyes and in the back of the head, resulting in lowerultrasound attenuation allowing certain brain structures to be imaged byultrasound. This may be accomplished, for example, by using transducerelements on ultrasound transducer assembly 220 that are located in theback of the head in the configuration shown in FIG. 4 , or by positing atransducer in the back of the head in the configuration shown in FIG.7A. By repeating the registration procedure using different ultrasoundimages, the accuracy of registration may be improved by selecting theultrasound image/pre-op image pair that produces the highest correlationvalues.

Selection of Target Regions

At any point in method 300 after pre-op images are obtained in step 305and before the configuration of subsets and transducers to be used aredetermined in step 330, one or more regions may be selected by aphysician in the pre-op image(s) for ultrasound energy to be deliveredin step 325 (defined as “target regions” above). In FIG. 10 , one suchtarget region is represented by a black dot 1025. Through the process ofregistration, the location of target region 1025 once it has beenselected, is known within coordinate system 1000. Once registration instep 320 has occurred, the coordinates of the target region may beknown, and this may be provided to one of the various ultrasound systemconfigurations discussed herein. It may be advantageous to select targetregions prior to beginning treatment of the patient in some scenarios.For example, a physician could perform this step prior to treatment.Without the time constraints that exist while treating a patient, morecareful consideration of the target region(s) could result in betteroutcomes.

Calculation of Delivery Subset

In step 330 of method 300, depending on the configuration of theultrasound system, calculations are made to either find the subset ofelements or to find the position and orientation of a transducer (eithermay be referred to as a delivery subset) that may be utilized to deliverultrasound energy to the target region(s). The goal in doing so is toallow ultrasound to be delivered to one or more locations at which it isdesired to promote the opening of the blood-brain barrier to allow drugsto enter brain tissue. These calculations may be used, for example, todetermine where a second transducer, such as transducer 1030 in FIG. 10, should be positioned in order to insonate the target region. In thisexample, if the calculations result in a position and orientationP2(X2,Y2,Z2,α2,β2,ϕ2) within reference coordinate system 1000,transducer 1030 may be placed at P2 in order to insonate target region1025.

In some embodiments, a number of factors may be taken into account inperforming the calculations mentioned above. Relevant factors include,but are not limited to, distance between the target region and thetransducer elements, attenuation of intervening tissue, orientation ofthe skull, and frequency characteristics of the transducer elements.Additionally, certain goals may be assigned. Example goals may includeselecting a delivery subset that can open the blood-brain barrier toallow drugs to be delivered with the least amount of acoustic power, orin another example, in the shortest amount of time given a specificacoustic power setting. These factors may influence the calculations indifferent ways, and may individually interact with one another. Forexample, choosing a subset that is closest to the target region may notalways be the optimal choice. The shape of the skull adjacent to thesesubsets may be such that it is at an angle to the plane containing thetarget region that results in significant mode conversion. As a result,sufficient energy may not be deposited at the target regions. In thisexample, it may be more desirable to select a subset that is fartheraway from the target region, but where less mode conversion will occur.

In some embodiments, the distance between a target region and thedelivery subset may be calculated using the pre-op images. Because thepre-op images are registered within the common frame of reference whichincludes the position of each element (regardless of its use for imagingor for facilitating treatment) and the location of the target region,the intervening distance may be easily obtained.

In some embodiments, the attenuation of intervening tissue at a certainpoint on the surface of the patient's head may be calculated using thepre-op images. Analysis of the pre-op images may reveal different layersof tissue between transducer elements and the target region. Bysegmenting these layers either automatically or manually, each layer maybe associated with attenuation parameters based on a priori data. Thus,it is possible to know the attenuation that may be experienced fordifferent delivery subset positions. This information may be applied toinfluence the choice of the delivery subset and/or to set amplitude orother transmit parameters.

3D Model Generation

A 3D computerized model of the patient's head may be generated by theultrasound system within head model generation module 510H. This modelmay be generated based on the registered pre-op images within the commonframe of reference. Patient head movement during treatment helps toillustrate a useful aspect of this concept. When patient head movementoccurs, the movement can be tracked by various sensors as describedelsewhere herein. The location of the model within the frame ofreference may be recalculated to reflect the new position within thereference coordinate system. This provides an advantage of not having toperform the registration steps 320 every time the position of thepatient's head is changed.

The head model may have various degrees of sophistication. For example,the 3D model may only include the outline of the skull corresponding tothe outermost layer of the skin. A more sophisticated example 3D modelmay include the outline of the skull and the thickness of the skull. Aneven more sophisticated example 3D model may include the various layersof the brain, including estimations of sound velocity in the variouslayers of brain tissue. The use of a computerized model is beneficialbecause it facilitates calculations and transformations, examples ofwhich are discussed below.

FIG. 13 illustrates an example application of a head model indetermining delivery subsets. A simple model 1300 may includeinformation about the outermost layer of head 410. Within this model,the location of target region 1310 may be known. In this non-limitingexample of a calculation for the selection of a treatment subset, thedistance from a region on the outermost layer of the skull to targetregion 1310 is the only factor taken into account. Distances fromregions A, B and C on the surface of the head to target region 1310 areindicated by lines 1320, 1330, and 1340, respectively. In this example,region B has the shortest distance and thus, a subset of elements aroundregion B may be chosen as the treatment subset.

In some embodiments, the computation of which region on the surface ofthe head has the shortest distance to target region 1310 may beperformed by computation of transmit subsets and transmit parametersmodule 510A. Each said region in this example embodiment may compriseone or more transducer elements.

An example embodiment of the calculation of the size of the treatmentsubset of transducer elements is now provided. In a simple example, thesize of the delivery subset may depend on the minimum acoustic powerneeded to open the blood-brain barrier. This minimum acoustic power maybe known a priori through experimentation or other means. Anotherrelevant factor that may influence the size of the subset is the effectsof beam propagation. Each transducer element has an angular directivitywhich may be dictated by a number of factors such as its size andfrequency of operation. Thus, elements that are very angular relative tothe target region may not be chosen for inclusion in the deliverysubset.

An example of software steps that may be implemented by module 510A todetermine the treatment subset in step 330 of method 300 are describedherein. First, the software may request that the human operator providea set of goals and relevant factors, such as delivering energy to aregion of the brain with a certain amount of acoustic power. These goalsand factors may be presented in the form of a drop down menu,checkboxes, or radio buttons to allow the operator to choose from one ormore options. The software may then generate a model of the patient'shead using the pre-op images and head model generation module 510H.Given the head model, and the prescribed goals, the location andorientation of ultrasound transducer elements that may be used todeliver ultrasound energy to the target region is calculated. This stepmay involve a process of optimization where the one or more goals andfactors are parameterized, and the optimization process involvesselecting a configuration yielding the highest “score”. Theparameterization process may optionally and beneficially take intoaccount user assigned weights. The final selection of the deliverysubset may be made manually be the human operator or automatically bythe software.

In ultrasound system 210 (see FIG. 4 ), following the selection of thedelivery subset, a subset of elements in ultrasound transducer assembly220 may be selected to operate in treatment mode. This may involveproviding instructions to all elements within subset 425A, for example,to begin transmitting ultrasound at a given transmit delay andfrequency. In the configuration shown in FIG. 7A, control signals mayarise from peripheral controls and I/O module 510G to inform the anglethat each joint of an arm 715 should be positioned. The final resultshould result in arm 100's end effector (i.e. where the transducer islocated) to be at the calculated position.

In the configuration shown in FIG. 7B, a human operator may manuallyposition transducer 760B such that it is placed at the desired locationwith guidance from software in ultrasound system 750. Sensors ontransducer 760B may detect whether the desired location has been reachedand may give feedback to the operator if adjustments are required.

Where the calculations and selection are performed automatically, inaddition to all of the factors discussed above, control and computationblock 510 may be guided by goals such as, but not limited to, selectinga subset or a transducer that can open the blood-brain barrier to allowdrugs to be delivered with the least amount of acoustic power, or in theshortest amount of time given a specific acoustic power setting.

Multiple Subsets

In some embodiments two or more subsets are generated. Each subsetcomprises one or more transducer elements that may be excited in acoordinated manner so that the ultimate effect is to open theblood-brain barrier at region(s) where their beam patterns intersect.Further, the subsets need not be contiguous. One advantage of multiplenon-contiguous subsets is that power delivered to the intervening tissuecan be minimized, while delivering the required power at one or moretarget region(s).

The calculation of which subsets are to be chosen to deliver ultrasoundenergy to a target region may depend on a number of factors such as, butnot limited to, the number of target regions and the size of eachregion. If the target region is small, it is possible that a subset withcontiguous elements may be selected. On the other hand, even for a smallregion, if it is determined that the intervening tissue may be atpotential risk (perhaps due to high acoustic power being needed for atarget region located far from the transducer elements), thennon-contiguous subsets may be more appropriate. Where there are multipletarget regions, or target regions that are large (that can subsequentlybroken up into multiple smaller regions), each region may be associatedwith its own calculations and its own delivery subset(s).

In the configurations illustrated in FIGS. 7A and 7B, it is noted thatit is possible that a subset of elements that is fewer than the totalelements present in a treatment transducer may be chosen. The size ofthis smaller subset may be chosen in a manner similar to the methodsdescribed for ultrasound transducer assembly 220 in FIG. 4 .

Alternative Determinations of Delivery Subset

In some embodiments, the delivery subset may be pre-determined, or itcan be found via reference to a look up table (LUT). As an example,gliomas are a common type of brain tumor that often develops in thebrainstem. Therefore, it may be advantageous to construct ultrasoundtransducer assemblies (such as one shown in FIG. 4 ) where treatmenttransducer elements are localized around the back of the head to deliverultrasound to the region of the blood-brain barrier that is closest tothe brainstem. No calculations would have to be performed in thisscenario to determine the subset of treatment elements to be used. Thismay reduce the cost of construction and maintenance of the device, aswell as reduce the computational complexity of the systems used duringtreatment.

In other embodiments, an ultrasound transducer assembly may includeseveral elements and a determination of the subset of elements to beused may be established through reference to a LUT. For example, basedon empirical analysis from a priori experimentation and analysis on apatient's pre-op image, a LUT can provide data indicating where on apatient's head is ultrasound energy most likely to be able to reach atarget region. A subset/subsets may then be chosen based on this resultto deliver the treatment. In configurations where a transducer is beingused (i.e. FIGS. 7A and 7B), reference to a LUT may be used to obtainthe desired positions and orientations based on relevant factors such asthe ones above.

In other embodiments, all available transducer elements may beconfigured to deliver ultrasound energy for treatment. Amplitude orother transmit parameters may be determined for each treatment based ona number of factors. These factors may include, but are not limited to,the distance from an element to the target region, the angle between theproduced ultrasound beam and the target region, and the properties ofintervening tissue. Where it is undesirable to insonate the targetregion using a certain elements, such elements may be set to transmit atan amplitude of near OdB.

Transmit Modes

In the various configurations of the systems described above, and inequivalent configurations, some transducer elements may be operable totransmit and receive whereas some other transducer elements may onlyhave the ability to transmit. FIG. 14A illustrates an example waveformproduced and received at a transducer element that is capable ofoperating in an imaging mode. In this mode, the element can bothtransmit and receive ultrasonic energy. Two graphs are illustrated inthis figure—one for transmit operations and another for receiveoperations. In region A, the element is excited by a two-cycle pulse ata frequency of 2 MHz at amplitude P. This is followed by region B, wherethe element receives echo data from the skull as a result of thetransmission. After a period of time, the element is excited again. Thiscycle is repeated as necessary to form images.

FIG. 14B illustrates an example waveform produced by an element that iscapable of operating in a treatment mode. This element is shown to beexcited by a much lower frequency, such as 0.5 MHz, and is also excitedfor a much longer time (8 cycles as shown in the figure). In this mode,the element does not need to receive any data and therefore does notform any images. Elements that are only capable of transmitting may beoperated only in a treatment mode, while an element that is capable ofboth transmitting and receiving may be operated in both imaging andtreatment modes.

There are several advantages to configuring transducer elements suchthat some are capable of transmitting and receiving, while others mayonly transmit. One advantage is the cost for implementing systemsdescribed herein may be reduced by making some elements capable of onlytransmitting. Here, the electronics and the processing needed forreceiving and processing ultrasound echo data need not be included forthese elements. It may be advantageous to place elements that thatoperate only in treatment mode (i.e. transmitting only) adjacent toareas where the attenuation of the skull is high and where imaging willtypically not be performed.

On the other hand, it may be advantageous to have elements that operateonly in imaging mode (i.e. transmitting and receiving) in somesituations. As will be explained elsewhere herein, these elements may beused to monitor the delivery of drug. Further, having elements that canboth operate in imaging mode and treatment mode can also be advantageousin some situations. It has been stated that most humans have lowacoustic attenuation acoustic windows adjacent to the temples. If thetarget regions were in the vicinity of these areas, the same elementsthat form images may also be best suited to insonate the target regions.

Contrast Agent Imaging

Contrast imaging is a technique used in ultrasound imaging to enhancesignal from the tissue. In contrast imaging, micro-bubbles are injectedinto the circulatory system. When insonated by ultrasound energy,provided that the bubbles do not break, the bubbles vibrate and reflectback energy at harmonic frequencies. Thus in a typical case, if theenergy of transmission is at a frequency of f0, the bubbles reflect backenergy at f0, and at other frequencies such as 2f0. The reflections fromthe bubbles are quite strong compared to typical reflection from tissueinterfaces. Images can thus be formed of the areas where the tissue isvascularized. For the purposes of imaging the brain and providingtreatment, microbubble techniques may be modified and adapted asdescribed below.

In some embodiments, different types of microbubbles are used. In anon-limiting example where two types of microbubbles are used, one typeof microbubble may be referred to as “imaging microbubbles” and theother may be referred to as “treatment microbubbles”. For greaterclarity, the microbubbles used in connection with opening theblood-brain barrier are referred to as treatment microbubbles. In someembodiments, these microbubbles may be supplied to the patient throughIV system 230 pictured in the ultrasound systems depicted in FIGS. 2, 7Aand 7B.

FIG. 15A shows an example method 1500 illustrating the use of imagingmicrobubbles. Initially, in step 1505, the patient is injected withimaging microbubbles. The microbubbbles travel to the brain where theycan be used to facilitate imaging the brain. For the sake of simplicity,it is assumed that all transducers/transducer elements in this exampleare capable of operating in both imaging and treatment modes. In step1510, images of the brain are obtained using ultrasound transducers withthe aid of the imaging microbubbles. In this example, the transmitparameters may be chosen such that the imaging microbubbles are causedto vibrate non-linearly. As the signals from the microbubbles aretypically strong, it may be possible to use higher receive frequenciesthan is typically used for imaging the brain. In a non-limiting example,the imaging transducer may operate at frequencies of 2 MHz transmit and4 MHz receive. Other combinations are also possible.

When performing imaging with the imaging microbubbles, other transmitand receive parameters such as, but not limited to, transmit power,transmit and receive apodization, receiver gain and receiver filter, mayalso be adjusted accordingly. These parameters, in particular thetransmit parameters, may be chosen such that the imaging bubbles arestable and do not break for a sufficient period of time before imagingcan be performed. Some parameters that are known to have an effect onmicrobubble stability are transmit power and transmit frequency. Thusfor imaging the brain, a low power transmission may be used that isdelivers sufficient energy to the targeted regions but not high enoughto break the microbubbles during the imaging period. Once images of thebrain are obtained in this manner, in step 1515, the target region orregions may be selected (using the methods described for step 325 ofmethod 300, for example). Prior to this, however, the images obtainedusing the imaging microbubbles may be used in registering the pre-opimage(s) to the ultrasound image (i.e. step 320 of method 300).

The use of microbubbles in ultrasound imaging compensate for theattenuation of the skull, increasing resolution and penetration depth.Therefore in some embodiments, imaging subsets or transducers are notrequired to be placed adjacent to low attenuation acoustic windows toform images of the brain when appropriate microbubbles are used. In somecases signals from the imaging microbubbles are strong enough that,target regions may be selected based entirely on the ultrasound image.For example, it may be possible that a target region or tumor in thebrain is highly vascularized. In these scenarios, it may be possible todiscern these areas in the ultrasound image when imaging microbubblesare used.

Treatment Microbubbles

After the target regions are selected in step 1515, method 1500continues to step 1520 where one or more transducers, or subsets oftransducer elements are selected and/or positioned for deliveringultrasound energy to a target region. The methods for accomplishing thismay be substantially similar to the ones described above for step 330 ofmethod 300 for the different ultrasound system configurations. Once thesubset(s) of elements are selected, or treatment transducer(s) areappropriately positioned, in step 1525, the patient is injected withtreatment microbubbles.

In some embodiments, the treatment microbubbles may contain the drug. Inother embodiments, the drug may be injected independent of the treatmentmicrobubbles, where the microbubbles serve to assist in the opening ofthe blood-brain barrier, but not to deliver drugs themselves. Now in box1530, the subset or subsets of elements that were chosen to be in thetreatment mode, are activated and the treatment microbubbles are causedto vibrate violently and or break, causing the blood-brain barrier toopen up to allow the passage of drugs.

The treatment microbubbles and the imaging microbubbles may be differentin a number of ways, and a partial list of these differences is nowprovided. Microbubbles can be manufactured so that they respond todifferent frequencies. For example, microbubbles that break at lowerfrequencies may be used in conjunction with treatment transducers.Certain microbubble characteristics such as, but not limited to, itssize and content may impact its response. In some embodiments, imagingmicrobubbles may be air or liquid filled whereas treatment microbubblesmay be filled with a drug. Other differences may exist and thesedifferences may be exploited to allow for the selection of ultrasoundsystem parameters such that the microbubbles facilitate imaging ortreatment delivery operations.

Method 1550 in FIG. 15B illustrates another variation of the conceptdescribed above where the imaging and treatment microbubbles are thesame. At step 1555, the patient is also injected with microbubbles.Method 1550 continues to step 1560 where images of the brain areobtained by choosing the ultrasound transducer transmit parameters suchthat the microbubbles facilitate imaging and do not to disrupt the bloodbrain barrier. These transmit parameters may include, but are notlimited to, a transmit power at or below a certain threshold, transmitfrequency, burst length, and pulse repetition frequency. The targetregions are selected in step 1565 followed by the selection of subset orsubsets of elements that are to be paced in treatment mode in step 1570.Now in step 1575, the drug, and optionally, more microbubbles, isinjected into the circulatory system. In step 1580, transmit parametersof the delivery subset are adjusted so that the microbubbles vibratemore violently and the blood-brain barrier is opened so that the drugmay be delivered.

Associate Drugs to a Transmit Sequence

In some embodiments, while a delivery subset is operating in treatmentmode, the transmit parameters may specifically be selected based on thedrug being delivered. As an example, through prior knowledge and/orexperimentation, it may be known that drug A is delivered optimally witha 10 cycle pulse at 0.5 MHz with a pulse repetition frequency of 1 KHzfor a period of 10 minutes, while drug B is delivered optimally with a15 cycle pulse at 0.25 MHz with a pulse repetition frequency of 1.2 KHzfor a period of 15 minutes. These optimal values may depend on a numberof factors such as, but not limited to, results obtained in animaltrials, results obtained in human trials, knowledge of drug composition,knowledge of microbubble composition, and body habitus of the patient.

In a non-limiting implementation of this concept, an imaging andtreatment system may include a bar code reader, a scanner, or anothertype of input device that reads information from a label on thecontainer of a drug. Once the system reads this information, the systemcan access memory storage such as a LUT where an optimal set of transmitparameters are stored for one or more drugs. This set of parameters mayinclude one or more parameters such as, but not limited to, frequency,transmit voltage, pulse length and pulse repetition frequency. Wheninstructed to do so, the imaging and treatment system may access thisstored information and operate ultrasound transducers in accordance withthese parameters. In other embodiments, an authorized medical personnelmay manually enter relevant information such as, but not limited to,information about the drug and body habitus.

In some embodiments, the system can be programmed such that if druginformation is not entered by one of the methods described above or byany other method, then ultrasound transducers are prevented fromoperating in treatment mode. According to a more specific embodiment,requiring information about the drug also allows the use of this actionto enable a billing function. The system may send a report or send anemail about how the responsibility for reimbursement for the drug and/ortreatment is to be shared amongst various parties.

Reducing or Eliminating Standing Waves

Standing waves within the cranial cavity can present a significant riskto patients. Standing waves may be created during both imaging andtreatment modes. Using non-uniform pulse repetition intervals may reduceor eliminate the possibility of creation of standing waves. While thismethod may be advantageous for imaging operations, it may not be idealfor the treatment mode. As explained above, drugs may be mosteffectively delivered with a certain set of transmit parameters. Thismay involve exposing the target region to ultrasound for a certainamount of time. In some embodiments, to provide the necessary exposuretime and to reduce or eliminate the possibility of generation ofstanding waves, different subsets (such as subset 425A in FIG. 4 ) ofelements may be used to deliver energy.

FIG. 16 illustrates an example embodiment of how different subsets maybe chosen to insonate the same target region. This method may facilitateeducing or eliminating standing waves while delivering the requireddosage of ultrasound to the target region. Target region 1605 isinitially insonated with transmit treatment pulses by subset 1610 for aperiod of time. The transmit delays of the elements of this subset arechosen such that region 1605 is insonated with subset 1610. The focusingof the ultrasound energy emitted by the elements in subset 1610 isdepicted by dashed lines 1620 that extend from subset 1610 to targetregion 1605. At a subsequent but successive time, subset 1615 may beused to transmit treatment pulses for another period of time. Thefocusing of the ultrasound energy emitted by the elements in this subsetis depicted by the solid lines 1625. Although FIG. 16 shows a region ofoverlap between subsets 1610 and 1615, configurations where there is nooverlap may also be utilized. Although only two subsets are illustratedin the figure, more than two subsets may be utilized in the performanceof this technique.

In some embodiments, software that implements the above method mayrequest the user to input the number of treatment subsets to be used.Goals for each subset may be further specified. Factors that may beprogrammed include, but are not limited to, maximum allowable off-axisangle, maximum time each subset may be active, and maximum amount ofsubset overlap. For example, an entered set of goals may be to findsubsets that are within 3° of the shortest distance to the target region(which may be specified as 0°) and with the least amount of overlap.Given these example instructions, the software may find subsets whosecenters are 3° or less from the shortest distance and then determine theappropriate size of these subsets, the order in which they are active,and the transmit parameters for each subset.

In some embodiments, such instructions may be entered as part of thesoftware programming process for an ultrasound system. In otherembodiments, a user may provide instructions for an ultrasound systemthrough a user interface. Once the instructions have been provided tothe ultrasound system, systems control module 510F may generate andprovide control signals to the selected subsets to transmit ultrasoundenergy to the patient.

Although illustrations of this method refer to subsets of transducerelements, the same concepts may be applied to configurations utilizingtransducers, such as those shown in FIGS. 7A and 7B. In these cases,multiple individual transducer elements capable of operating intreatment mode may be grouped together to accomplish these methods. Inother embodiments, the groups of treatment elements may be located indifferent transducers.

Building a Volumetric Image

In conventional ultrasound imaging systems, 3D or 4D images aretypically created by a 2D transducer with the elements being in the sameplane, a 1D array being “wobbled” in an elevation dimension, or a 1Drotating transducer such as those used in transesophageal imaging.Building a volumetric image may be desirable in the ultrasound systemsdescribed herein because a more representative model of the brain'sstructures allow for higher accuracy in performing comparisons withpre-op images during the registration process. In another example, wherethe resolution of structures obtained by ultrasound imaging is highenough (e.g. through the use of microbubbles), a volumetric ultrasoundimage may allow for a target region to be selected. However, in theconfiguration shown in FIG. 4 for example, the elements withinultrasound transducer assembly 220 are arranged differently compared totypical transducer arrangements. Therefore, different scanningtechniques may be required to form 3D or 4D images with the systemsdescribed herein.

In some embodiments, different imaging planes may be used with the samesubset of elements. In any subset of elements containing multipleelements, the elements can be arranged electronically in various wayssuch as, but not limited to, in an array configuration or in a concavecurvilinear configuration. The orientation of the curvilinearconfiguration may also be chosen as desired. An example non-limitingembodiment of this concept is shown in FIG. 17 . Here an array ofelements 1700 is illustrated. This array of elements may be part of thesubset 420A of ultrasound transducer assembly 220 in FIG. 4 , forexample. As each of the elements within this array may be independentlycabled and therefore controllable via an ultrasound system, variousscanning planes may be achieved electronically. Two such example groupsare illustrated by 1710 and 1720. Any element that does not liecompletely within the dashed lines may be excluded from the group. Theelectronic delays calculated by the modules 510A and 510B may be suchthat the scanning planes of each of groups 1710 and 1720 areperpendicular to the plane of FIG. 17 (into the page), but parallel tothe long side of the boundaries of these groups.

Through these methods, multiple scanning planes may be generated. Theimages obtained from these scanning planes would interrogate differentanatomical planes. Thus by generating multiple planes along differentscanning planes, a volume may be scanned and a volumetric image begenerated.

In other embodiments, different imaging planes may be used to fill inmissing volumetric information. These different imaging planes need nothave the same orientation or angle or location with respect to eachother. However, because an image plane's 6DOF position is known in acommon reference frame, it can be placed alongside other images in thesame coordinate system such that a volumetric image can be constructed.This method to construct a volume may be advantageous because data aboutthe entire volume of the brain is often incomplete. Partial volumereconstruction as described allows for the available image data to beput towards meaningful uses. In a more specific embodiment,interpolation of RF echo data can be used in a volume construction dataset to fill-in missing data elements.

Synthetic Aperture Imaging

Any suitable ultrasound imaging technology may be applied. Example,ultrasound imaging technologies include beamforming technologies andsynthetic aperture imaging technologies

Synthetic aperture imaging allows for the formation of an image withfewer transducer elements compared to what is needed in a fullypopulated aperture. The concepts of synthetic aperture imaging may bemodified for the purposes of producing ultrasound images of the brain.In some embodiments, different transducer elements may be used for eachtransmit operation. After each transmission, the echo may be received atmultiple elements, and the echo data may be digitized and stored. Anultrasound system may then process the various pulse-echo response pairsto synthesize and construct a higher resolution image than wouldnormally be possible with the number of elements involved.

Another advantage that can be gained by using synthetic aperture imagingis that as different elements are being used for transmission, thepossibility of generating standing waves is reduced or eliminated.Methods of synthetic aperture imaging described herein may be applied toall of the various ultrasound system configurations discussed.

Insonating Regions Close to the Surface of the Skull

Additional challenges are encountered when attempting to insonate targetregions close to the surface of the skull. For example it is difficultto position elements such that they are parallel to the surface of theskull at the point of contact and still direct energy to the targetregion. Focusing the ultrasonic energy may also be challenging due tothe low frequency and short distance between the target region and theelements. In some embodiments, subsets of elements that are relativelydistant from the target region are be chosen such that these subsets areparallel or nearly parallel to the skull at the point of contact. In anon-limiting example, a target region on the left side of the head nearthe ears may be insonated by a subset of elements from the right side ofthe head. Using appropriate transmit parameters, the blood-brain barrieron the left side can be made to open up to allow drugs to pass. Inaddition to location, transmit parameters such, as but not limited to,frequency and power may be adjusted to insonate such target regions froma distance.

In another embodiment, transducers (such as those shown in FIGS. 7A and7B) may be positioned at a distance away from the skull. A stand-offmaterial may be placed between said transducers and the skull such thatthe two components may remain coupled. Stand-off materials are typicallysoft and gelatinous. The stand-off material may be selected such thatessentially no attenuation of ultrasound occurs through the material. Ina non-limiting example, the speed of sound through this material may be1540 m/s. Additionally, the thickness of the material may be anywherebetween 1 cm to 5 cm. Through this technique, the transducers can beplaced in a parallel or nearly parallel manner to the skull. As thedistance between the target region and the elements is larger, issues offocusing at short distances are minimized or removed. It should be notedthat these methods of operating transducer elements close to a targetregion are equally applicable to transducers or subsets operating inimaging mode.

Stand-off materials may also be used optionally and beneficially inconfigurations where there are one or more transducer elements dispersedover an assembly (such as that shown in FIG. 4 ). In some embodiments, alayer of stand-off material may be placed around and in contact with apatient's head. Ultrasound transducer assembly 220, for example, may beplaced over the material, with transducer elements 415 in contact withit. The properties and thicknesses of the stand-off material may beselected such that it is able to be in contact with elements 415 anddoes not exert a reaction force high enough that the ability to controlthe orientation of elements 415 is inhibited. This allows for standardsized ultrasound transducer assemblies to be used across a range ofpatient head sizes.

Subset Specific System Parameters

In some embodiments, each subset or transducer may be operated with itsown set of parameters such as, but not limited to, transmit parameters,receive parameters, number of elements, element configuration, aperturedimensions. In a non-limiting example, a subset operating in treatmentmode in the vicinity of the temporal bone may operate at a higherfrequency, for example 2 MHz, compared to a subset near the top of thehead that may operate at 0.5 MHz. Similarly, the active aperture nearthe temporal bone may include elements that are generally within acircle of radius 20 mm whereas the aperture near the top of the head maygenerally be rectangular in shape with dimensions of 70 mm by 10 mm.

Subset or transducer parameters may be calculated automatically ormanually. In some embodiments, automatic calculations may be carried outby control and computation block 510. These calculations may includeinformation about the location of the subset/transducer on the skull andmay calculate parameters based on this information. Thus, parameters maybe optimized for each subset or transducer depending on location andwhat imaging or treatment goals have been defined. Regardless of whetherthe subset or transducer parameters are calculated manually orautomatically, transmit and receive parameter computation modules 510Aand 510B may ensure that no safety limits such as acoustic or thermallimits are violated. Application of these concepts may allow for theaccommodation of the local conditions of the skull, the tissue in thevicinity of the elements, and the tissue that is insonated.

Fiducials

Some patients may have objects in their head, such as screws or dentalimplants, that may be observable in ultrasound, MRI, and CT scans. Insome embodiments, such objects may be used as fiducial markers toimprove the accuracy of registration. In a non-limiting example, adental implant may be imaged by one or more transducer elements. If thelocation of the transducer element(s) were known, an ultrasoundtransducer assembly (see ultrasound transducer assembly 220 in FIG. 4 )or transducer can be placed in relation to the dental implant. If thelocation of the same implant is known in a pre-op image, thenregistration of an ultrasound image to the pre-op image may be performedagainst the dental implant. This method offers an alternative toregistering pre-op and ultrasound images that does not requiretransducer elements to be located specifically at low acousticattenuation windows.

Confirmation of Dose Delivery

Contrast agents such as microbubbles may be used to facilitate thedelivery of drugs and to obtain confirmation that a drug has beendelivered. In some embodiments, ultrasound transducers or subsets may beinterspersed with elements that are specially tuned to receive energyreleased from microbubbles as the blood-brain barrier opens up. Thisenergy may be in the sub-harmonic range or the harmonic range. In a morespecific embodiment, one or more receive only elements are tuned todetect these specific frequencies to confirm the delivery of anultrasound dose and/or drug.

Display and User Interface

FIG. 18 illustrates a non-limiting example of a display and userinterface 1800 that may be provided to an authorized person such as adoctor to interact with an example ultrasound system described above. Inthis configuration, the display may contain four windows, 1810, 1830,1850 and 1870. In window 1810, the ultrasound image from a lowattenuation acoustic window may be displayed. Image 1815 is obtainedfrom a low attenuation low attenuation acoustic window with circle ofWillis 1820 pictured inside it. In window 1830, pre-op image 1835 may besimultaneously displayed. Pre-op image 1835 may be a 3D rendering ofimages obtained from MRI scans, for example. The circle of Willislabelled in the pre-op image as 1840, but physically it is the samestructure as 1820 in ultrasound image 1815.

As initial steps not shown in this illustration of a user interface1800, the user may be requested by the ultrasound system to importpre-op images of the patient's brain. The user may then be instructed toplace imaging transducers at low attenuation acoustic windows to allowthe ultrasound system to collect images. These steps relate to steps 305and 310 of method 300 respectively. In other embodiments of a userinterface, instruction and confirmation messages may be provided by theultrasound system.

A suitable user interface may be provided to allow the user to registerthe two images. FIG. 18 illustrates workflow window 1850 with a numberof user selectable boxes 1855, 1860, and 1865. The user may select box1855 to begin the process of registration of an ultrasound image withthe pre-op image(s). After this selection, user interface 1800 may askthe user to select an ultrasound image that may be used forregistration. If live imaging through a low attenuation acoustic windowis being performed, the system may halt live imaging and provide theuser the option of scrolling through images in window 1810 that havebeen just recently acquired and stored, and choosing an image from thisset of images. In a conventional ultrasound imaging system, the storingfunction is called the “cine” function. Once an appropriate image isselected, the user may be asked to outline a structure within the image(such as circle of Willis 1820 in this example). This process is calledsegmentation.

Segmentation may be carried out automatically, manually, or in acombination of the two. In the present example, a doctor may provide aninitial outline of the circle of Willis 1820. Ultrasound systemsdescribed herein may optionally and beneficially provide a color Dopplerimaging mode to aid the segmentation process. Operating in this modeallows for blood flow in the circle of Willis to be detected anddisplayed, making the boundaries of the vessels that form the circle ofWillis easily distinguishable. The user can therefore easily draw anoutline of the Circle of Willis using the colored vessels against theblack and white image of the rest of the brain tissue. The ultrasoundsystem may proceed with the next step, or alternatively use the manuallydrawn boundaries as a basis for segmentation algorithms programmedinternally to generate a more accurate segmentation. This selectionprocess relates to step 310 of method 300.

Once segmentation is complete, user interface 1800 may request for theselection of a plane that most closely matches the segmented image.Again, this may be carried out manually, automatically or in acombination of the two. In an automatic process, the ultrasound systemmay look within pre-op image 1835 to try and find an image plane thatmost closely matches the segmented ultrasound image. In a combinedoperation, user interface 1800 may display a fused ultrasound and MRIimage in window 1830, after automatically determining a plane within theMR image, and ask the user to make a determination on if that match wasacceptable.

Window 1870 may be used to display messages and accept inputs from theuser. Selectable boxes such as accept box 1875 and reject box 1880 maybe displayed to accept inputs from the user. The user may thereforeindicate acceptance of the match between the ultrasound and pre-opimage, or may direct the ultrasound system to continue to find a bettermatch. Other user interface elements may also be provided to the user toguide the matching process. The selection of a desirable plane in thepre-op image may be used as the starting point in the registrationprocess (this may reflect step 320C2 in method 320C, for example). Asthe ultrasound system performs the process of registration, it maydisplay a status indicator in message window 1885. Message window maynotify the user when registration is completed and/or provide furtherinstructions.

Subsequently in window 1850, user interface 1800 may ask the user toselect a target region in box 1860, corresponding to step 315 in method300. As described previously, the target region may be chosen in the MRimage. In this illustration, the user may point to a region such asregion 1845 and select it as the target region. It should be noted thatthis step may be performed at any point after a pre-op image has beenobtained. Its inclusion in these steps only serves to illustrate how itmay be performed alongside other steps in a common user interface.

The ultrasound system may automatically select a region around the areaselected by the user. This region selection may be guided bypreprogrammed data entered into the ultrasound system a priori.Alternatively, user interface 1800 may allow the user to modify theboundary of the automatically selected target region, or to select itentirely manually. After the user indicates they are satisfied with thesize and shape of the target region (through the use of message box 1885and boxes 1875 and 1880 in window 1870), user interface 1800 may thenask the user to begin the treatment. This process reflects an exampleembodiment of step 325 of method 300 and may provide the coordinates ofthe target regions as output. Start treatment button 1865, which mayhave previous been greyed out, may become selectable, and when selectedmay trigger a number of actions.

After starting treatment, the ultrasound system may calculate thedelivery subset as explained above in step 330 of method 300. Followingthis, the ultrasound system may move a treatment transducer to theappropriate location on the head in the configuration shown in FIG. 7A,or select the treatment subset(s) in the configuration shown in FIG. 4 .Where a treatment transducer is controlled manually, such as in theconfiguration shown in FIG. 7B, the current treatment transducercoordinates may be displayed in the message window 1885 along with thedesired calculated coordinates. When the user has correctly placed thetransducer at the desired coordinates, message window 1885 may display amessage indicating this. Other methods of guiding the user to thedesired location are possible.

Once the treatment elements are selected or the treatment transducer isin the appropriate location, the ultrasound system may send signals tothe IV pump and treatment transducer elements to coordinate the timingof the delivery of ultrasound with the operation of the IV pump.Depending on signals obtained from the transducer and/or other sensors,user interface 1800 may display when the blood-brain barrier has openedup, or other relevant status updates. This information may be calculatedin real-time or may be based on empirical analysis from a prioriexperimentation. A message may be displayed in message window 1885 oncea drug has been delivered indicating that treatment is completed or thatthe user should proceed to treat another region.

Interpretation of Terms

Unless the context clearly requires otherwise, throughout thedescription and the

-   -   “comprise”, “comprising”, and the like are to be construed in an        inclusive sense, as opposed to an exclusive or exhaustive sense;        that is to say, in the sense of “including, but not limited to”;    -   “connected”, “coupled”, or any variant thereof, means any        connection or coupling, either direct or indirect, between two        or more elements; the coupling or connection between the        elements can be physical, logical, or a combination thereof;    -   “herein”, “above”, “below”, and words of similar import, when        used to describe this specification, shall refer to this        specification as a whole, and not to any particular portions of        this specification;    -   “or”, in reference to a list of two or more items, covers all of        the following interpretations of the word: any of the items in        the list, all of the items in the list, and any combination of        the items in the list;    -   the singular forms “a”, “an”, and “the” also include the meaning        of any appropriate plural forms.

Words that indicate directions such as “vertical”, “transverse”,“horizontal”, “upward”, “downward”, “forward”, “backward”, “inward”,“outward”, “vertical”, “transverse”, “left”, “right”, “front”, “back”,“top”, “bottom”, “below”, “above”, “under”, and the like, used in thisdescription and any accompanying claims (where present), depend on thespecific orientation of the apparatus described and illustrated. Thesubject matter described herein may assume various alternativeorientations. Accordingly, these directional terms are not strictlydefined and should not be interpreted narrowly.

Implementations of the invention may comprise any of specificallydesigned hardware, configurable hardware, programmable data processorsconfigured by the provision of software (which may optionally comprise“firmware”) capable of executing on the data processors, special purposecomputers or data processors that are specifically programmed,configured, or constructed to perform one or more steps in a method asexplained in detail herein and/or combinations of two or more of these.Examples of specifically designed hardware are: logic circuits,application-specific integrated circuits (“ASICs”), large scaleintegrated circuits (“LSIs”), very large scale integrated circuits(“VLSIs”), and the like. Examples of configurable hardware are: one ormore programmable logic devices such as programmable array logic(“PALs”), programmable logic arrays (“PLAs”), and field programmablegate arrays (“FPGAs”)). Examples of programmable data processors are:microprocessors, digital signal processors (“DSPs”), embeddedprocessors, graphics processors, math co-processors, general purposecomputers, server computers, cloud computers, mainframe computers,computer workstations, and the like.

For example, one or more data processors in a control circuit for asystem as described herein or for an ultrasound machine as describedherein or for a module as described herein may implement methods asdescribed herein by executing software instructions in a program memoryaccessible to the processors and/or by processing data according tologic configured in a logic circuit or configurable device such as anFPGA and/or by processing data in an ASIC or other logic circuitconfigured to perform the method steps described herein.

A group of modules as described herein may be implemented using separatehardware (e.g. separate processors and/or configurable logic circuitsand/or hard-wired logic circuits) but two or modules may also share someor all of a hardware platform. For example two or more modules may beimplemented by common data processor(s) and/or configurable logiccircuits and/or hard-wired logic circuits configured by softwareinstructions or otherwise to perform the functions of each of the two ormore modules.

Processing may be centralized or distributed. Where processing isdistributed, information including software and/or data may be keptcentrally or distributed. Such information may be exchanged betweendifferent functional units by way of a communications network, such as aLocal Area Network (LAN), Wide Area Network (WAN), or the Internet,wired or wireless data links, electromagnetic signals, or other datacommunication channel.

While processes or blocks are presented in a given order, alternativeexamples may perform routines having steps, or employ systems havingblocks, in a different order, and some processes or blocks may bedeleted, moved, added, subdivided, combined, and/or modified to providealternative or subcombinations. Each of these processes or blocks may beimplemented in a variety of different ways. Also, while processes orblocks are at times shown as being performed in series, these processesor blocks may instead be performed in parallel, or may be performed atdifferent times.

Some aspects of the invention may be provided in the form of a programproduct. The program product may comprise any non-transitory mediumwhich carries a set of computer-readable instructions which, whenexecuted by a data processor, cause the data processor to execute amethod of the invention. Program products according to the invention maybe in any of a wide variety of forms. The program product may comprise,for example, non-transitory media such as magnetic data storage mediaincluding floppy diskettes, hard disk drives, optical data storage mediaincluding CD ROMs, DVDs, electronic data storage media including ROMs,flash RAM, EPROMs, hardwired or preprogrammed chips (e.g., EEPROMsemiconductor chips), nanotechnology memory, or the like. Thecomputer-readable signals on the program product may optionally becompressed or encrypted.

In some implementations, the invention may be implemented in software.For greater clarity, “software” includes any instructions executed on aprocessor, and may include (but is not limited to) firmware, residentsoftware, microcode, and the like. Both processing hardware and softwaremay be centralized or distributed (or a combination thereof), in wholeor in part, as known to those skilled in the art. For example, softwareand other modules may be accessible via local memory, via a network, viaa browser or other application in a distributed computing context, orvia other means suitable for the purposes described above.

Where a component (e.g. a software module, processor, assembly, device,circuit, etc.) is referred to above, unless otherwise indicated,reference to that component (including a reference to a “means”) shouldbe interpreted as including as equivalents of that component anycomponent which performs the function of the described component (i.e.,that is functionally equivalent), including components which are notstructurally equivalent to the disclosed structure which performs thefunction in the illustrated exemplary implementations of the invention.

Specific examples of systems, methods and apparatus have been describedherein for purposes of illustration. These are only examples. Thetechnology provided herein can be applied to systems other than theexample systems described above. Many alterations, modifications,additions, omissions, and permutations are possible within the practiceof this invention. This invention includes variations on describedimplementations that would be apparent to the skilled addressee,including variations obtained by: replacing features, elements and/oracts with equivalent features, elements and/or acts; mixing and matchingof features, elements and/or acts from different implementations;combining features, elements and/or acts from implementations asdescribed herein with features, elements and/or acts of othertechnology; and/or omitting combining features, elements and/or actsfrom described implementations.

It is therefore intended that claims hereafter introduced areinterpreted to include all such modifications, permutations, additions,omissions, and sub-combinations as may reasonably be inferred. The scopeof the claims should not be limited by the preferred implementations setforth in the examples, but should be given the broadest interpretationconsistent with the description as a whole.

What is claimed is:
 1. An ultrasound treatment system operable todeliver ultrasound energy to a patient's brain, the ultrasound treatmentsystem comprising: a treatment ultrasound transducer comprising aplurality of treatment elements, the treatment ultrasound transducerlocatable to deliver ultrasound into the head of the patient; a datastore; one or more position sensors configured to detect relativemovement between the head of the patient and the treatment ultrasoundtransducer; and a data processor configured to: determine a registrationtransformation which transforms coordinates of at least one targetregion identified in a previously obtained image in the data store tocoordinates of the ultrasound treatment system; determine an initialtreatment ultrasound transducer location from which to deliverultrasound treatment energy from the treatment ultrasound transducer tothe at least one target region based at least in part on theregistration transformation; and monitor output from the one or moreposition sensors to determine detected relative movement between thehead of the patient and the treatment ultrasound transducer; determinean updated treatment ultrasound transducer location from which todeliver ultrasound treatment energy from the updated treatmentultrasound transducer to the at least one target region based at leastin part on the detected relative movement; and control the at least onetreatment ultrasound transducer to deliver treatment ultrasound energyfrom the updated treatment ultrasound transducer location to the atleast one target region with an energy sufficient to open the bloodbrain barrier of the patient at the at least one target region.
 2. Thesystem of claim 1 wherein the data processor is configured to positionthe treatment ultrasound transducer to the updated treatment ultrasoundtransducer location.
 3. The system of claim 1 wherein the treatmentultrasound transducer comprises a plurality of elements and the dataprocessor is configured to determine a subset of the plurality ofelements to deliver the treatment ultrasound energy based at least inpart on the updated treatment ultrasound transducer location.
 4. Thesystem of claim 1 wherein the data processor is configured to monitoroutput from the one or more position sensors and determine the updatedtreatment ultrasound transducer location after commencing delivery ofthe treatment ultrasound energy.
 5. The system of claim 4 wherein thedata processor is configured to position the treatment ultrasoundtransducer to the updated treatment ultrasound transducer location aftercommencing delivery of the treatment ultrasound energy.
 6. The system ofclaim 4 wherein the treatment ultrasound transducer comprises aplurality of elements and the data processor is configured to determinea subset of the plurality of elements to deliver the treatmentultrasound energy based at least in part on the updated treatmentultrasound transducer location after commencing delivery of thetreatment ultrasound energy.
 7. The system of claim 1 wherein the dataprocessor is configured to monitor output from the one or more positionsensors and determine the updated treatment ultrasound transducerlocation on a periodic basis during delivery of the treatment ultrasoundenergy.
 8. The system of claim 1 wherein the data processor isconfigured to monitor output from the one or more position sensors anddetermine the updated treatment ultrasound transducer location beforecommencing delivery of the treatment ultrasound energy.
 9. The system ofclaim 8 wherein the data processor is configured to position thetreatment ultrasound transducer to the updated treatment ultrasoundtransducer location before commencing delivery of the treatmentultrasound energy.
 10. The system of claim 8 wherein the treatmentultrasound transducer comprises a plurality of elements and the dataprocessor is configured to determine a subset of the plurality ofelements to deliver the treatment ultrasound energy based at least inpart on the updated treatment ultrasound transducer location beforecommencing delivery of the treatment ultrasound energy.
 11. The systemof claim 1 wherein the data processor is configured, after commencingdelivery of the treatment ultrasound energy, to monitor output from theone or more position sensors to determine whether the detected relativemovement is greater than a threshold and, if such a determination ismade, to take corrective action related to the delivery of treatmentultrasound energy.
 12. The system of claim 11 wherein the data processoris configured to take corrective action which comprises positioning thetreatment ultrasound transducer to the updated treatment ultrasoundtransducer location.
 13. The system of claim 11 wherein the treatmentultrasound transducer comprises a plurality of elements and the dataprocessor is configured to take corrective action which comprisesdetermining an updated subset of the plurality of elements to deliverthe treatment ultrasound energy based at least in part on the updatedtreatment ultrasound transducer location.
 14. The system of claim 11wherein the data processor is configured to take corrective action whichcomprises at least one of: discontinuing delivery of the treatmentultrasound energy; and providing a warning message.
 15. A method forconfiguring an ultrasound treatment system, the method comprising:providing a treatment ultrasound transducer comprising a plurality oftreatment elements, the treatment ultrasound transducer locatable todeliver ultrasound into the head of the patient; providing one or moreposition sensors configured to detect relative movement between the headof the patient and the treatment ultrasound transducer; by a dataprocessor: determining a registration transformation which transformscoordinates of at least one target region identified in a previouslyobtained image to coordinates of the ultrasound treatment system;determining an initial treatment ultrasound transducer location fromwhich to deliver ultrasound treatment energy from the treatmentultrasound transducer to the at least one target region based at leastin part on the registration transformation; monitoring output from theone or more position sensors to determine detected relative movementbetween the head of the patient and the treatment ultrasound transducer;determining an updated treatment ultrasound transducer location fromwhich to deliver ultrasound treatment energy from the treatmentultrasound transducer to the at least one target region based at leastin part on the detected relative movement; and controlling the at leastone treatment ultrasound transducer to deliver treatment ultrasoundenergy from the updated treatment ultrasound transducer location to theat least one target region with an energy sufficient to open the bloodbrain barrier of the patient at the at least one target region.
 16. Themethod of claim 15 comprising positioning the treatment ultrasoundtransducer to the updated treatment ultrasound transducer location. 17.The method of claim 15 wherein the treatment ultrasound transducercomprises a plurality of elements and the method comprises determining asubset of the plurality of elements to deliver the treatment ultrasoundenergy based at least in part on the updated treatment ultrasoundtransducer location.
 18. The method of claim 15 comprising monitoringoutput from the one or more position sensors and determining the updatedtreatment ultrasound transducer location after commencing delivery ofthe treatment ultrasound energy.
 19. The method of claim 18 comprisingpositioning the treatment ultrasound transducer to the updated treatmentultrasound transducer location after commencing delivery of thetreatment ultrasound energy.
 20. The method of claim 18 wherein thetreatment ultrasound transducer comprises a plurality of elements andthe method comprises determining a subset of the plurality of elementsto deliver the treatment ultrasound energy based at least in part on theupdated treatment ultrasound transducer location after commencingdelivery of the treatment ultrasound energy.